HIV integrase inhibitors: cyclic pyrimidinone compounds

ABSTRACT

The invention encompasses a series of pyrimidinone compounds which inhibit HIV integrase and thereby prevent viral integration into human DNA. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses intermediates useful for making the pyrimidone compounds. Additionally, pharmaceutical compositions and methods for treating those infected with HIV are encompassed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. non-provisionalapplication Ser. No. 11/110,589, filed Apr. 20, 2005, now U.S. Pat. No.7,273,859 and claims the benefit of U.S. provisional application No.60/570,348, filed May 12, 2004.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) has been identified as theetiological agent responsible for acquired immune deficiency syndrome(AIDS), a fatal disease characterized by destruction of the immunesystem and the inability to fight off life threatening opportunisticinfections. Recent statistics (UNAIDS: Report on the Global HIV/AIDSEpidemic, December 1998), indicate that as many as 33 million peopleworldwide are infected with the virus. In addition to the large numberof individuals already infected, the virus continues to spread.Estimates from 1998 point to close to 6 million new infections in thatyear alone. In the same year there were approximately 2.5 million deathsassociated with HIV and AIDS.

There are currently a number of antiviral drugs available to combat theinfection. These drugs can be divided into three classes based on theviral protein they target and their mode of action. In particular,saquinavir, indinavir, ritonavir, nelfinavir and amprenavir arecompetitive inhibitors of the aspartyl protease expressed by HIV.Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavirare nucleoside reverse transcriptase inhibitors that behave as substratemimics to halt viral cDNA synthesis. And nevaripine, delavirdine andefavirenz are non-nucleoside reverse transcriptase inhibitors, whichinhibit the synthesis of viral cDNA via a non-competitive (oruncompetitive) mechanism. When used alone these drugs are effective inreducing viral replication. The effect, however, is only temporary asthe virus readily develops resistance to all known agents. Currently,combination therapy has proven very effective at both reducing virus andsuppressing the emergence of resistance in a number of patients. In theUS, where combination therapy is widely available, the number ofHIV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman,A. C.; Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.;Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853-860).

Unfortunately, not all patients are responsive and a large number failthis therapy. In fact, approximately 30-50% of patients ultimately failcombination therapy. Treatment failure in most cases is caused by theemergence of viral resistance. Viral resistance in turn is caused by therapid turnover of HIV-1 during the course of infection combined with ahigh viral mutation rate. Under these circumstances incomplete viralsuppression caused by insufficient drug potency, poor compliance due tothe complicated drug regiment as well as intrinsic pharmacologicalbarriers to exposure provides fertile ground for resistance to emerge.More disturbing are recent findings which suggest that low-levelreplication continues even when viral plasma levels have dropped belowdetectable levels (<50 copies/ml) (Carpenter, C. C.; Cooper, D. A.;Fischl, M. A.; Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M.S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D.D.; Saag, M. S.; Schechter, M.; Schooley, R. T.; Thompson, M. A.; Vella,S.; Yeni, P. G.; Volberding, P. A. JAMA 2000, 283, 381-390). Clearlythere is a need for new antiviral agents, preferably targeting otherviral enzymes to reduce the rate of resistance and suppress viralreplication even further.

HIV expresses three enzymes: reverse transcriptase, an aspartylprotease, and integrase. All three are targets for treating AIDS and HIVinfection. HIV integrase catalyzes insertion of the viral cDNA into thehost cell genome, which is a critical step in the viral life cycle. HIVintegrase inhibitors belonging to a class of diketo acid compoundsprevented viral integration and inhibited HIV-1 replication in cells(Hazuda et al. Science 2000, 287, 646). And recently, HIV integraseinhibitors have been accepted into clinical trials for treating AIDS andHIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Paisand Burke Drugs Fut. 2002, 27, 1101).

DESCRIPTION OF THE INVENTION

The invention encompasses a series of pyrimidinone compounds whichinhibit HIV integrase and thereby prevent viral integration into humanDNA. This action makes the compounds useful for treating HIV infectionand AIDS. The invention also encompasses intermediates useful for makingthe pyrimidone compounds. Additionally, pharmaceutical compositions andmethods for treating those infected with HIV are encompassed.

One aspect of the invention is a compound of Formula I

where:

-   R¹ is C₁₋₆(Ar¹)alkyl;-   R² is hydrogen, C₁₋₆alkyl, or OR⁶;-   R³ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆haloalkoxy,    CON(R⁶)(R⁶), SOR⁷, SO₂R⁷, SO₂N(R⁶)(R⁶), or Ar²;-   R⁴ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆haloalkyl, or C₁₋₆haloalkoxy;-   R⁵ is hydrogen, halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆haloalkyl, or C₁₋₆haloalkoxy;-   R⁶ is hydrogen or C₁₋₆alkyl;-   R⁷ is C₁₋₆alkyl;-   R⁸ and R⁹ taken together are CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂,    CH₂CH₂CH₂CH₂CH₂, CH₂CH₂CH₂CH₂CH₂CH₂, OCH₂CH₂, CH₂OCH₂, OCH₂CH₂CH₂,    CH₂OCH₂CH₂, OCH₂CH₂CH₂CH₂, CH₂OCH₂CH₂CH₂, CH₂CH₂OCH₂CH₂,    OCH₂CH₂CH₂CH₂CH₂, CH₂OCH₂CH₂CH₂CH₂, CH₂CH₂OCH₂CH₂CH₂, N(R⁶)CH₂CH₂,    CH₂N(R⁶)CH₂, N(R⁶)CH₂CH₂CH₂, CH₂N(R⁶)CH₂CH₂, N(R⁶)CH₂CH₂CH₂CH₂,    CH₂N(R⁶)CH₂CH₂CH₂, CH₂CH₂N(R⁶)CH₂CH₂, N(R⁶)CH₂CH₂CH₂CH₂CH₂,    CH₂N(R⁶)CH₂CH₂CH₂CH₂, or CH₂CH₂N(R⁶)CH₂CH₂CH₂;-   Ar¹ is

-   Ar² is tetrazolyl, triazolyl, imidazolyl, pyrazolyl, pyrrolyl, or    dioxothiazinyl, and is substituted with 0-2 substituents selected    from the group consisting of amino, oxo, halo, cyano, and C₁₋₆alkyl;    and-   X—Y-Z is C(R⁸)(R⁹)CH₂CH₂, C(R⁸)(R⁹)CH₂CH₂CH₂, C(R⁸)(R⁹)CH₂CH₂CH₂CH₂,    C(R⁸)(R⁹)OCH₂, C(R⁸)(R⁹)OCH₂CH₂, or C(R⁸)(R⁹)OCH₂CH₂CH₂;    or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a compound of Formula I where X—Y-Zis C(R⁸)(R⁹)CH₂CH₂, C(R⁸)(R⁹)CH₂CH₂CH₂, or C(R⁸)(R⁹)CH₂CH₂CH₂CH₂.

Another aspect of the invention is a compound of Formula I according tothe following structures.

Another aspect of the invention is a compound of Formula I where X—Y-Zis C(R⁸)(R⁹)OCH₂, C(R⁸)(R⁹)OCH₂CH₂, or C(R⁸)(R⁹)OCH₂CH₂CH₂.

Another aspect of the invention is a compound of Formula I according tothe following structures.

Another aspect of the invention is a compound of Formula I where R⁸ andR⁹ taken together are CH₂CH₂CH₂, CH₂CH₂CH₂CH₂, CH₂CH₂CH₂CH₂CH₂,CH₂CH₂CH₂CH₂CH₂CH₂, CH₂OCH₂CH₂, CH₂CH₂OCH₂CH₂, CH₂N(R⁶)CH₂CH₂, orCH₂CH₂N(R⁶)CH₂CH₂.

Another aspect of the invention is a compound of Formula I where R¹ is(Ar¹)methyl.

Another aspect of the invention is a compound of Formula I where R² ishydrogen.

Another aspect of the invention is a compound of Formula I where R³ isfluoro, chloro, methyl, CON(R⁶)(R⁶), or Ar².

Another aspect of the invention is a compound of Formula I where R⁴ ishydrogen, fluoro, chloro, or methyl.

Another aspect of the invention is a compound of Formula I where R⁵ ishydrogen.

Another aspect of the invention is a compound of Formula I where Ar¹ is

For a compound of Formula I, any scope of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸and R⁹ taken together, and X—Y-Z can be used independently with anyscope of any other substituent.

Another aspect of the invention is a compound of Formula II.

where

-   R^(6a) is hydrogen, C₁₋₆alkyl, C₁₋₆(Ar¹)alkyl, ArC₁₋₆, C—(C═C)n-C,    C₁₋₆—O—C₁₋₆—O—C₁₋₆, C₁₋₆—O—C₁₋₆—Ar, C(Ar)₂₋₃, CO(C₁₋₆)₁₋₃, or COAr;    and-   P is hydrogen, mesyl, tosyl, allyl, benzyl, fluorenylmethyl,    allyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl,    tri(C₁₋₆alkyl)silyl, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, or    C₁₋₆alkoxycarbonyl, ArC₁₋₆, C—(C═C)n-C, C₁₋₆—O—C₁₋₆—O—C₁₋₆,    C₁₋₆—O—C₁₋₆—Ar, CO(C₁₋₆)₁₋₃, COAr, or C(Ar)₂₋₃.

Another aspect of the invention is a compound of Formula II where R^(6a)is hydrogen, C₁₋₆alkyl, or C₁₋₆(Ar¹)alkyl; and P is hydrogen, mesyl,tosyl, allyl, benzyl, fluorenylmethyl, allyloxycarbonyl,benzyloxycarbonyl, fluorenylmethoxycarbonyl, tri(C₁₋₆alkyl)silylC₁₋₆alkyl, C₁₋₆alkylcarbonyl, or C₁₋₆alkoxycarbonyl.

Some compounds of the invention are

N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-a]pyrimidine]-2′-carboxamide;

N-[(4-fluoro-3-methylphenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-a]pyrimidine]-2′-carboxamide;

N-[[2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[5-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-imidazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[3-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-(phenylmethyl)-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(4-methylphenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(4-methoxyphenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6H)¹-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(4-chlorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(3-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(2-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(3,4-dimethylphenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(3,4-dichlorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(2,4-dimethoxyphenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(4-fluoro-3-methylphenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(3-fluoro-4-methylphenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[1-(4-fluorophenyl)ethyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(2,5-difluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(2,5-dichlorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[5-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6¹′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

7′,8′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-spiro[cyclobutane-1,9′(6′H)-[4H]pyrido[1,2-α]pyrimidine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,8′(4′H)-pyrrole[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,8′(4′H)-pyrrolo[1,2-α]pyrimidine]-2′-carboxamide;

N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,8′(4′H)-pyrrolo[1,2-α]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,8′(4′H)-pyrrolo[1,2-α]pyrimidine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(6′H)-[4H]pyrido[1,2-a]pyrimidine]-2′-carboxamide;

N-(phenylmethyl)-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluoro-3-methylphenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(methylthio)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

6′,7′-dihydro-3′-hydroxy-N-[(4-methylphenyl)methyl]-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-chlorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(3,4-dichlorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(3,4-dimethylphenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

6′,7′-dihydro-3′-hydroxy-N-[(4-methoxyphenyl)methyl]-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(2-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(2,4-dimethoxyphenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(3-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(3-fluoro-4-methylphenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[(2-(dimethylamino)sulfonyl]-4-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[5-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[2-(4-fluorophenyl)ethyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[3-(4-fluorophenyl)propyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

6′,7′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

6′,7′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-4,5,6′,7′-tetrahydro-3′-hydroxy-4′-oxo-spiro[furan-3(2H),9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluoro-3-methylphenyl)methyl]-4,5,6′,7′-tetrahydro-3′-hydroxy-4′-oxo-spiro[furan-3(2H),9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-4,5,6′,7′-tetrahydro-3′-hydroxy-4′-oxo-spiro[furan-3(2H),9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′)-carboxamide;

N-[[4-fluoro-2-(methylthio)phenyl]methyl]-4,5,6′,7′-tetrahydro-3′-hydroxy-4′-oxo-spiro[furan-3(2H),9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′)-carboxamide;

N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluoro-3-methylphenyl)methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(2,4-dimethoxyphenyl)methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide

N-[(3,4-dimethylphenyl)methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,6′,7-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-2-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[2-[(dimethylamino)sulfonyl]-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2-carboxamide;

N-[(4-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[piperidine-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-4,5,6′,7′-tetrahydro-3′-hydroxy-4′-oxo-spiro[furan-3(2H),9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;and

N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

and salts and solvates of these compounds.

Some other compounds of Formula I include

N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-[4-(1,1-dimethylethyl)-1H-1,2,3-triazol-1-yl]-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(2-oxo-1-azetidinyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

[5-fluoro-2-[[[(2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxospiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepin]-2′-yl)carbonyl]amino]methyl]phenyl]-phosphonicacid, dimethyl ester;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

2,3,5,6,7′,8′-hexahydro-3′-hydroxy-N-[[2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

6′,7′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(2-oxo-1-azetidinyl)phenyl]methyl]-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

6′,7′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;

N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1--c][1,4]oxazine]-2′-carboxamide;

N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;

N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;

and pharmaceutically acceptable salts and solvates of these compounds.

“Alkyl,” “alkoxy,” “haloalkyl,” and related terms for other hydrocarbonand substituted hydrocarbon substituents include straight and branchedisomeric configurations. A term such as “C₁₋₆(R)alkyl” means a straightor branched alkyl group of 1 to 6 carbons substituted with thesubstituent R. “Haloalkyl” and related terms for halogenatedsubstituents include all permutations of halogenation, frommonohaloalkyl to perhaloalkyl. “Aryl” means an aromatic ring system andincludes carbocyclic and heterocyclic systems. Some substituents aredivalent, for example, X—Y-Z. Divalent substituents which are asymmetriccan be attached to the parent molecule in either of the configurations.

“Dioxothiazinyl” means

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

The invention also includes all solvated forms of the compounds,particularly hydrates. Solvates do not contribute significantly to thephysiological activity or toxicity of the compounds and as such functionas pharmacological equivalents. Solvates may form in stoichiometricamounts or may form from adventitious solvent or a combination of both.One type of solvate is hydrate, and some hydrated forms includemonohydrate, hemihydrate, and dihydrate.

The invention includes all tautomeric forms of the compounds. An exampleof a tautomeric pair is shown below.

Some of the compounds of the invention exist in stereoisomeric forms.The invention includes all stereoisomeric forms of the compoundsincluding enantiomers and diastereromers. An example of enantiomers isshown below. Methods of making and separating stereoisomers are known inthe art.

Synthetic Methods

The compounds of this invention can be made by various methods known inthe art including those of the following schemes and in the specificembodiments section. The variables shown in the schemes (for example, X,n, and P) are separate from and should not be confused with thevariables in the claims or the rest of the specification. The variablesin the schemes are meant only to illustrate how to make some of thecompounds of this invention. “X” and “n” include alkylene spacers whichmay contain ether or amino functionalities. “P” may include anappropriate protecting group. Starting materials can be made usingmethods known in the art.

Biological Methods

To evaluate in-vitro activity against HIV-integrase, 5 pmole of biotinlabeled substrate DNA was bound to 100 μg of Streptavidin coated PVT SPAbeads (Amersham Pharmacia Biotech). Recombinant integrase (0.26 ng) wasincubated with the beads for 90 min at 37° C. Unbound enzyme was removedby washing the complex followed by addition of inhibitors and 0.1 mmolof P33 labeled target DNA. The reaction was stopped by adding EDTA to afinal concentration of 10 mM. Samples were counted in TopCountNXT(Packard) and the CPM was used as a measure of integration. The reactioncondition was as described in Engelman, A. and Craigie, R. J. Vitrol.1996, 69, 5908. The sequences of substrate and target DNA were describedin Nucleic Acid Research 1994, 22, 1121. Using this assay, the compoundof this invention were found to have an IC₅₀ from less than 0.1 μM (seeTables 1 and 1a).

TABLE 1 HIV Integrase Inhibition Example IC₅₀ 1 A 2 A 3 A 4 A 5 A 6 A 7A 8 B 9 A 10 A 11 A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 B 20 A 21 A 22B 23 B 24 B 25 B 26 B 27 A 28 A 29 A 30 B 31 B 32 A 33 A 34 A 35 B 36 A37 A 38 A 39 A 40 A 41 A 42 A 43 B 44 A 45 A 46 B 47 B 48 A 49 A 50 A 51A 52 A 53 A 54 A 55 A 56 B 57 A 58 B 59 A 60 A 61 B 62 A 63 B 64 B 65 A66 A 67 A 68 B 69 A 70 A 71 B 72 A 73 A 74 B 75 B 76 A 77 A 78 A 79 A 80A 81 A 82 A 83 B 84 A 85 A 86 B 87 A 88 B 89 A 90 B 91 A Activity. A:0.001-0.01 μM; B: 0.01-0.1 μM.

TABLE 1a HIV Integrase Inhibition Example IC₅₀ 92 A 93 A 94 B 95 A 96 A97 B 98 A 99 A 100 B 101 A 102 B 103 B 104 A 105 A 106 A 107 B 108 A 109A 110 A 111 B 112 A 113 A 114 A 115 A 116 B 117 B 118 A 119 A 120 B 121B 122 A 123 A 124 A 125 A 126 A 127 B 128 B 129 A 130 A 131 A 132 AActivity. A: 0.001-0.01 μM; B: 0.01-0.1 μM

Pharmaceutical Composition and Methods of Use

The compounds of this invention inhibit HIV integrase. HIV integraseinhibitors have been reported to prevent viral integration and inhibitedHIV-1 replication in cells (Hazuda et al. Science 2000, 287, 646).Recently, HIV integrase inhibitors have been accepted into clinicaltrials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther.Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).

Accordingly, another aspect of the invention is a method for treatingHIV infection in a patient comprising administering a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, with a pharmaceutically acceptablecarrier.

Another aspect of the invention is a method for treating HIV infectionin a patient comprising administering a therapeutically effective amountof a compound of Formula I, or a pharmaceutically acceptable salt orsolvate thereof, with a therapeutically effective amount of at least oneother agent used for treatment of AIDS or HIV infection. Some suitableagents are nucleoside HIV reverse transcriptase inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, HIV proteaseinhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, andHIV integrase inhibitors.

Another aspect of the invention is a composition comprising atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, with apharmaceutically acceptable carrier.

“Combination,” “coadministration,” “concurrent,” and similar termsreferring to the administration of compounds of Formula I with at leastone anti-HIV agent mean that the components are part of a combinationantiretroviral therapy or highly active antiretroviral therapy (HAART)as understood by practitioners in the field of AIDS and HIV infection.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of AIDS and HIV infection. In general, the goals of treatmentare suppression of viral load, restoration and preservation ofimmunologic function, improved quality of life, and reduction ofHIV-related morbidity and mortality.

“Patient” means a person infected with the HIV virus and suitable fortherapy as understood by practitioners in the field of AIDS and HIVinfection.

“Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” andrelated terms are used as understood by practitioners in the field ofAIDS and HIV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of Formula I or its pharmaceutically acceptable salt and apharmaceutically acceptable carrier and may contain conventionalexipients. A therapeutically effective amount is that which is needed toprovide a meaningful patient benefit. Pharmaceutically acceptablecarriers are those conventionally known carriers having acceptablesafety profiles. Compositions encompass all common solid and liquidforms including capsules, tablets, losenges, and powders as well asliquid suspensions, syrups, elixers, and solutions. Compositions aremade using common formulation techniques, and conventional excipients(such as binding and wetting agents) and vehicles (such as water andalcohols) are generally used for compositions.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agentswill be present in a unit range similar to agents of that class usedclinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other antiretroviral agents will be present in a unitrange similar to agents of that class used clinically. Typically, thisis 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other antiretroviral agents used clinically. Typically,the daily dose will be 1-100 mg/kg body weight daily. Generally, morecompound is required orally and less parenterally. The specific dosingregime, however, will be determined by a physician using sound medicaljudgment.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith other agents useful in treating AIDS and HIV infection. Some ofthese agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIVnucleoside reverse transcriptase inhibitors, HIV non-nucleoside reversetranscriptase inhibitors, HIV protease inhibitors, budding andmaturation inhibitors, immunomodulators, and anti-infectives. In thesecombination methods, the compound will generally be given in a dailydose of 1-100 mg/kg body weight daily in conjunction with other agents.The other agents generally will be given in the amounts usedtherapeutically. The specific dosing regime, however, will be determinedby a physician using sound medical judgment.

Table 2 lists some agents useful in treating AIDS and HIV infectionwhich are suitable for this method.

TABLE 2 DRUG NAME MANUFACTURER INDICATION ANTIVIRALS 097 Hoechst/BayerHIV infection, AIDS, (non-nucleoside ARC reverse transcriptaseinhibitor) Amprenavir Glaxo Wellcome HIV infection, AIDS, 141 W94 ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, AIDS, GW 1592 ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC,in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection, ARC, AL-721 Ethigen PGL HIV positive,AIDS (Los Angeles, CA) Alpha Interferon Glaxo Wellcome Kaposi's sarcomaHIV in combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha (Rockville, MD) aberrantInterferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'1 Cancer Institute AIDS-associated diseases BMS-232623 Bristol-MyersSquibb/ HIV infection, AIDS, (CGP-73547) Novartis ARC (proteaseinhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, AIDS,(CGP-61755) Novartis ARC (protease inhibitor) CI-1012 Warner-LambertHIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes,papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral, CMV retinitis DelaviridinePharmacia-Upjohn HIV infection, AIDS, (RT inhibitor) ARC Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomaticJapan) ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combinationwith AZT/d4T DMP-450 AVID HIV infection, AIDS, (proteaseinhibitor) (Camden, NJ) ARC Efavirenz DuPont Merck HIV infection, AIDS,(DMP 266) ARC (-)6-Chloro-4-(S)- cyclopropylethynyl- 4(S)-trifluoro-methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE (non-nucleosideRT inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA)Famciclovir Smith Kline herpes zoster, herpes simplex FTC EmoryUniversity HIV infection, AIDS, (reverse ARC transcriptase inhibitor) GS840 Gilead HIV infection, AIDS, (reverse ARC transcriptase inhibitor)HBY097 Hoechst Marion HIV infection, AIDS, (non-nucleoside Roussel ARCreverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection,AIDS, ARC Recombinant Triton Biosciences AIDS, Kaposi's sarcoma, Human(Almeda, CA) ARC Interferon Beta Interferon alfa-n3 Interferon SciencesARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer InstituteHIV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection,AIDS, (reverse ARC, also with AZT transcriptase inhibitor) LobucavirBristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,AIDS, (protease inhibitor) Pharmaceuticals ARC Nevirapine BoeheringerHIV infection, AIDS, (RT inhibitor) Ingleheim ARC Novapren NovaferonLabs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDSOctapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis,HIV Phosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, (protease inhibitor)ARC Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, AIDS, Tech (Houston, TX) ARC Ritonavir Abbott HIV infection,AIDS, (protease inhibitor) ARC Saquinavir Hoffmann- HIV infection, AIDS,(protease inhibitor) LaRoche ARC Stavudine; d4T Bristol-Myers Squibb HIVinfection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir GlaxoWellcome Genital HSV & CMVinfections Virazole Viratek/ICN asymptomaticHIV- Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIVinfection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC,Kaposi's sarcoma, in combination with other therapies Tenofovir GileadHIV infection, AIDS disoproxil, fumarate salt (Viread ®) (reversetranscriptase inhibitor) Combivir ® GSK HIV infection, AIDS (reversetranscriptase inhibitor) abacavir succinate GSK HIV infection, AIDS (orZiagen ®) (reverse transcriptase inhibitor) Reyataz ® Bristol-MyersSquibb HIV infection, AIDS (atazanavir) Fuzeon Roche/Trimeris HIVinfection, AIDS, (Enfuvirtide, T-20) viral fusion inhibitor Trizivir ®HIV infection, AIDS Kaletra ® Abbott HIV infection, AIDS, ARCIMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia UpjohnAdvanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)CL246, 738 American Cyanamid AIDS, Kaposi's sarcoma Lederle Labs EL10Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharmBlocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, incombination w/TNF (tumor necrosis factor) Granulocyte Genetics InstituteAIDS Macrophage Colony Sandoz Stimulating Factor GranulocyteHoechst-Roussel AIDS Macrophage Colony Immunex Stimulating FactorGranulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZTStimulating Factor HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's sarcoma, (New Orleans, LA) ARC, PGL IMREG-2 Imreg AIDS,Kaposi's sarcoma, (New Orleans, LA) ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma AIDS,Muramyl-Tripeptide Amgen in combination w/AZT Granulocyte ColonyStimulating Factor Remune Immune Response Immunotherapeutic Corp. rCD4Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARChybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma, AIDS, Alfa 2a in combination w/AZTARC SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of oral Nystatin Pastille candidiasis Ornidyl MerrellDow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate(Rosemont, IL) (IM & IV) Trimethoprim Antibacterial Trimethoprim/sulfaAntibacterial Piritrexim Burroughs Wellcome PCP treatment PentamidineFisons Corporation PCP prophylaxis Isethionate for Inhalation SpiramycinRhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm.Histoplasmosis; R51211 cryptococcal meningitis TrimetrexateWarner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcomaRecombinant Ortho Pharm. Corp. Severe anemia assoc. Human with AZTtherapy Erythropoietin Recombinant Serono AIDS-related wasting, HumanGrowth cachexia Hormone Megestrol Acetate Bristol-Myers Squibb Treatmentof anorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and NutritionPharmaceuticals malabsorption related to AIDS

DESCRIPTION OF SPECIFIC EMBODIMENTS

1-(3-chloropropyl)cyclopentanecarbonitrile. To a stirred solution ofcyclopentanecarbonitrile (1.04 mL, 10 mmol) in THF (20 mL) at −78° C.was added LiHMDS (1M in THF, 11 mL) via syringe. After 30 min,1-chloro-3-iodopropane (1.6 mL, 15 mmol) was added at once and slowlywarmed to room temperature. After 20 h, the reaction mixture wasquenched with saturated ammonium chloride (1 mL), diluted with EtOAc(100 mL), dried (MgSO₄), filtered and concentrated to give intermediate1 as yellow oil which was used in the next step without furtherpurification.

To a stirred mixture of intermediate 1 from previous experiment andhydroxylamine hydrochloride (1.39 g, 20 mmol) in 1:1 EtOH/water (30 mL)was added sodium carbonate (1.6 g, 15 mmol) over 5 min. Then, thereaction mixture was stirred to 80° C. for 15 h and concentrated todryness. The resulting white residue was re-dissolved into 1:1EtOH/water (30 mL) and diethyl acetylenedicarboxylate (2.4 mL, 15 mmol)was added. After 1 h, the reaction mixture was diluted with water (50mL) and extracted with EtOAc (3×50 mL). The combined EtOAc extractsdried (Na₂SO₄), filtered and concentrated to give brown oil. Flashchromatography using 9:1, 4:1 and 7:1 Hexanes/EtOAc mixtures affordedintermediate 2 as pale yellow oil (1.03 g, 30%). ¹H NMR (500 MHz, CDCl₃)δ: 4.34-4.11 (4H, m), 3.50-3.46 (1H, m), 3.38-3.34 (1H, m), 3.31 (1H, d,J=16.2 Hz), 2.91 (1H, d, J=16.2 Hz), 2.23-2.13 (2H, m), 1.95-1.89 (2H,m), 1.74-1.69 (2H, m), 1.62 (2H, t, J=5.9 Hz), 1.54-1.48 (2H, m),1.34-1.23 (8H, m). HRMS (M+H) calcd for C₁₇H₂₇N₂O₅: 339.1920; found:339.1923.

A solution of intermediate 2 (1.0 g, 2.955 mmol) in 3, 4-dichlorotoluene(10 mL) was heated at 210° C. for 15 h. Then, the reaction mixture wasconcentrated under vacuum and the residue was purified by preparativeHPLC using MeOH/water containing 0.1% TFA (gradient elution). Thefractions containing the product were combined and concentrated toafford intermediate 3 as a dark paste (0.8639 g, 28.6%).¹H NMR (500 MHz,CDCl₃) δ: 10.75 (1H, br s), 4.43 (2H, q, J=7.0 Hz), 4.03 (2H, t, J=5.8Hz), 2.25-2.20 (2H, m), 1.99-1.93 (4H, m), 1.79-1.64 (6H, m), 1.42 (3H,t, J=7.0 Hz),. HRMS (M+H) calcd for C₁₅H₂₁N₂O₄: 293.1501; found:293.1513.

Tetrahydro-2H-pyran-4-carbonitrile. A solution oftetrahydro-4H-pyran-4-one (25 g, 250 mmol) and toluenesulfonylmethylcyanide (53.7 g, 275 mmol) dissolved in ethylene glycol dimethylether (1L) was cooled to 0° C. Added dropwise over 30 min was a solution ofpotassium t-butoxide (56 g, 500 mmol) dissolved in t-butanol (350 mL)and ethylene glycol dimethylether (150 mL). After stirring the resultingmixture for 3 h at room temp, diethyl ether (1 L) was added and theorganic phase was washed with saturated aqueous NaHCO₃. The organicphase was dried (Na₂SO₄) and concentrated. The residue was distilled at39° C. 1.7 mm Hg to give the title compound as a colorless oil (10.87 g,39% yield). ¹H NMR (300 MHz, CDCl₃) δ: 3.91-3.83 (2H, m), 3.61-3.54 (2H,m), 2.89-2.80 (1H, m), 1.97-1.78 (4H, m).

4-(3-chloropropyl)-tetrahydro-2H-pyran-4-carbonitrile. To a stirredsolution of 1 M LiHMDS (25 mL, 25 mmol) in THF (10 mL) at −78° C. wasadded dropwise a solution of intermediate 4 (2.23 g, 20 mmol) in THF (15mL) over 10 minutes. After 40 min, 1-chloro-3-iodopropane (2.7 mL, 25mmol) was added at once, stirred at −78° C. for 1 h and 4 h roomtemperature. Then the reaction mixture was diluted with ether (100 mL),washed with water (20 mL) and brine (20 mL), dried (Na₂SO₄), filteredand concentrated to give yellow oil which was purified by flash columnchromatography using 10-30% EtOAc/Hexanes to afford the productintermediate 5 as a colorless liquid (3.737 g, 99%). ¹H NMR (500 MHz,CDCl₃) δ: 3.97 (2H, dd, J=11.3, 3.7 Hz), 3.71 (2H, td, J=12.2, 1.8 Hz),3.61 (2H, t, J=6.3 Hz), 2.05-1.98 (2H, m), 1.88 (2H, dd, J=13.4, 1.8Hz), 1.77-1.74 (2H, m), 1.65-1.59 (2H, m).

A mixture of intermediate 5 (1.83 g, 9.75 mmol) and NaI (3.0 g, 20 mmol)was stirred at ambient temperature for 1 h. To this reaction mixture wasadded 50% aqueous hydroxylamine (1 mL, 10.87 mmol mmol) and stirred forthree-days at ambient temperature. To this was added diethylacetylenedicarboxylate (1.6 mL, 10 mmol) and stirred for 1 h. Then, thereaction mixture was diluted with EtOAc (100 mL) washed with water (50mL), brine (10 mL), dried (Na₂SO₄), filtered and concentrated to giveyellow oil. Flash chromatography using 10-50% EtOAc/Hexanes afforded thedesired intermediate 6 as pale yellow oil (0.627 g, 18% %). ¹H NMR (500MHz, CDCl₃) δ: HRMS (M+H) calcd for C₁₇H₂₇N₂O₅:; found. ¹H NMR (500 MHz,CDCl₃) δ: 4.32-4.20 (2H, m), 4.14 (2H, q, J=7.0 Hz), 3.86 (1H, td,J=11.0, 2.7 Hz), 3.79-3.70 (3H, m), 3.52-3.46 (1H, m), 3.38-3.34 (1H,m), 3.26 (1H, d, J_(AB)=16.2 Hz), 2.97 (1H, d, J_(AB)=16.2 Hz),2.06-1.89 (4H, m), 1.66-1.66 (2H, m), 1.60-1.53 (2H, m), 1.30 (3H, t,J=7.0 Hz), 1.24 (3H, t, J=7.0 Hz).

A solution of intermediate 6 (1.0 g, 2.955 mmol) in cyclohexylbenzene(25 mL) was heated at 200° C. for 15 h. Then, the reaction mixture wasconcentrated under vacuum and the residue was purified by preparativeHPLC using MeOH/water containing 0.1% TFA (gradient elution). Thefractions containing the product were combined and concentrated toafford intermediate 7 as an off-white solid (0.1263 g, 23%).¹H NMR (500MHz, CDCl₃) δ: 10.35 (1H, br s), 4.45 (2H, q, J=7.0 Hz), 4.09-4.05 (2H,m), 4.01-3.99 (2H, m), 3.74-3.69 (2H, m), 2.35-2.29 (2H, m), 2.02-1.93(4H, m), 1.59-1.54 (2H, m), 1.44 (3H, t, J=7.0 Hz). HRMS (M+H) calcd forC₁₅H₂₁N₂O₄: 309.1451; found: 309.1463.

(E)-2-{[1-(2-Hydroxyethoxy)cyclopentanecarboximidoyl]-aminooxy}but-2-enedioicacid diethyl ester. A stirred mixture of cyclopentanone ethylene ketal(12.82 g, 100 mmol) and ZnI₂ (45 mg, catalytic) was placed in water bathand to this was added trimethylsilyl cyanide (13.35 mL, 100 mmol) viasyringe over 10 min. After 16 h, EtOH (100 mL) followed by 50% aqueoushydroxylamine (6.43 mL, 100 mmol) was added and stirred at 80° C. for 2h. Then, the reaction mixture was cooled in ice-water bath and diethylacetylenedicarboxylate (16 mL, 100 mmol) was added over 5 min. Then,cooled bath removed, stirred for 4 h at room temperature andconcentrated to give intermediate 8 as a dark-brown oil which was usedin the next step without purification. LRMS (M+H) calcd for C₁₆H₂₇N₂O₇:359.2; found: 359.2.

5-Hydroxy-2-[3-(2-hydroxy-ethoxy)tetrahydrofuran-3-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxylicacid ethyl ester. A xylenes (200 ml) solution of crude intermediate 8(100 mmol) was heated at reflux for 24 h, cooled and concentrated. Theresulting dark-residue was stirred with 0.5 M Na₂CO₃ (150 mL) for 30 minand extracted with EtOAc (3×50 mL). The combined organic phases werere-extracted with 0.5 M Na₂CO₃ (50 mL) and EtOAc extracts discarded. Thecombined aqueous layers was carefully acidified with conc. HCl (20 mL)and extracted with CH₂Cl₂ (4×50 mL). The combined CH₂Cl₂ layers dried(Na₂SO₄/activated charcoal), filtered and concentrated to give brownsolid which triturated with ether and filtered to afford intermediate 9as a light brown powder (11.81 g, 38%). This material is contaminatedwith about 15% of an identified impurity whose M+1=295. LRMS (M+H) calcdfor C₁₄H₂₁N₂O₆: 313.32; found: 313.27.

To a stirred solution of crude intermediate 9 (11.67 g) in THF (100 mL)at 5° C. was added MsCl (8.7 mL, 112.4 mmol) followed by Et3N (15.8 mL,112.5 mmol). The resulting turbid reaction mixture was stirred for 4 hwhile allowing it to warm to room temperature. Then diluted with EtOAc(200 mL), washed with water (2×50 mL), brine (50 mL), dried (Na₂SO₄),filtered and concentrated to give viscous yellow oil. This oil wasre-dissolved in anhydrous EtOH (100 mL) and stirred with K₂CO₃ (4.15 g,30 mmol). After 4 h, the viscous slurry was diluted with EtOAc (150 mL)and continued stirring for additional 1 h. Then, the reaction mixturewas filtered and concentrated to give white solid which was trituratedwith ether, and filtered to afford intermediate 10 as a white fluffysolid (8.284 g, 64%). ¹H NMR (500 MHz, CDCl₃) δ: 4.43 (2H, q, J=7.0 Hz),3.99 (4H, s), 3.53 (3H, s), 2.33-2.28 (2H, m), 2.09-2.05 (2H, m),1.93-1.82 (4H, m), 1.40 (3H, t, J=7.0 Hz). HRMS (M+H) calcd forC₁₅H₂₁N₂O₇S: 373.1069; found: 373.1053.

To a stirred suspension of intermediate 10 (0.6861 g, 1.84 mmol) in THF(50 mL) was added 1M EtONa/EtOH (10 mL). After 1 h, the resulting yellowsolution was concentrated, acidified with 1 M aq. HCl (20 mL), extractedwith CH₂Cl₂ (3×35 mL). The combined organic layers dried (Na2SO4),filtered and concentrated to give intermediate 11 as a brown solid(0.4668 g, 86%). ¹H NMR (500 MHz, CDCl₃) δ: 10.49 (1H, s), 4.44 (2H, q,J=7.0 Hz), 4.03-3.97 (4H, m), 2.28-2.22 (2H, m) 2.06-2.01 (2H, m),1.93-1.81 (4H, m), 1.42 (3H, t, J=7.0 Hz). HRMS (M+H) calcd forC₁₄H₁₉N₂O₅: 295.1294; found: 295.1293.

Dihydrofuran-3(2H)-one. A mixture of 3-hydroxyfuran (24 g, 272 mmol) andTEMPO (0.86 g, 5.5 mmol) in CH₂Cl₂ (175 mL) and KBr (7.141 g, 60 mmol)in water was vigorously stirred and cooled in an ice-water bath. The pHof NaOCl (commercial grade bleach, 600 mL, 806 mmol) was adjusted to 9.5by dissolving NaHCO₃ (8.632 g, 102.75 mmol) immediately before use. ThisNaOCl solution was added over 40 min while keeping the internaltemperature of the reaction mixture between 0° C. and 5° C. After 2 h,the greenish-yellow organic phase was separated and aqueous phase wassaturated with NaCl and extracted with CH₂Cl₂ (4×100 mL). The combinedorganic phases was washed with 10% HCl aq. (1×300 mL) containing KI (12g) and 10% aq. Na₂CO₃ (2×150 mL). The organic layer dried (Na2SO4),filtered and concentrated to give intermediate 12 as a pale yellowliquid (15.79 g, 67%) which was used without purification. ¹H NMR (500MHz, CDCl₃) δ: 4.24 (2H, t, J=7.3 Hz), 3.86 (2H, s), 2.49 (2H, t, J=7.3Hz).

1,4,7-Trioxaspiro[4.4]nonane. A mixture of intermediate 12 (15.79 g,183.5 mmol), ethylene glycol (16.7 mL, 300 mmol) and cat. TsOH.H₂O (100mg) in benzene (100 mL) was heated at reflux using Dean-Stark trap.After 17 h, the reaction mixture was cooled, diluted with ether (150mL), washed with sat. Na₂CO₃ and brine (50 mL each), dried (Na₂SO₄),filtered and concentrated to give yellow liquid. Distillation underreduced pressure afforded intermediate 13 as a yellow liquid (19.13 g,80%). ¹H NMR (500 MHz, CDCl₃) δ: 3.9.4 (2H, t, J=7.0 Hz), 3.94-3.90 (4H,m), 3.68 (2H, s), 2.09 (2H, t, J=7.0 Hz).

(E)-2-{[3-(2-Hydroxy-ethoxy)tetrahydrofuran-3-carboximidoyl]-aminooxy}but-2-enedioicacid diethyl ester. Prepared according to the procedure for intermediate8. Yield: 38%; viscous yellow paste. 1H NMR (500 MHz, CDCl₃) δ: 5.78(1H, d, J=7.6 Hz), 5.59 (1H, br s), 5.38 (1H, s), 4.37-4.27 (2H, m),4.20-4.13 (2H, m), 4.03-3.87 (4H, m), 3.79-3.75 (2H, m), 3.53-3.45 (2H,m), 1.60 (1H, br s), 1.38-1.23 (6H, m). HRMS (M+H) calcd for C₁₅H₂₅N₂O₈:361.1611; found: 361.1620.

Prepared according to the procedure for intermediate 11. Yield: 29%;brown solid. ¹H NMR (500 MHz, CDCl₃) δ: 10.63 (1H, br s), 4.44 (2H, q,J=7.0 Hz), 4.18-4.11 (4H, m), 4.08-4.01 (4H, m), 2.66-2.60 (1H, m),2.35-2.30 (1H, m), 1.41 (3H, t, J=7.0 Hz). HRMS (M+H) calcd forC₁₃H₁₇N₂O₆: 297.1087; found: 297.1071.

1,4,8-Trioxa-spiro[4.5]decane. A mixture of tetrahydro-4-pyranone (10 g,99.9 mmol), ethylene glycol (20 mL, 150 mmol) and catalytic toluenesulfonic acid was refluxed in benzene (120 mL) for 5 h. After cooling toroom temp, the benzene layer was decanted from the dark oil in thebottom of the flask and was concentrated. The resulting oil was taken upin methylene chloride and shaken in a separatory funnel. The CH₂Cl₂layer was decanted from the insoluble oil. The CH₂Cl₂ layer wasconcentrated to give the intermediate 16 as a pale yellow oil (11.62 g,81% yield). ¹H-NMR (300 MHz, CDCl₃) δ: 3.91 (4H, s), 3.71 (4H, t, J=5.5Hz), 1.68 (4H, t, J=5.7 Hz).

(E)-2-{[4-(2-Hydroxyethoxy)tetrahydropyran-4-carboximidoyl]-aminooxy}but-2-enedioicacid diethyl ester. Prepared according to the procedure for intermediate8. Yield: 60%; yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ: 5.72 (1H, d,J=22.7 Hz), 5.50 (1H, bs), 5.29 (1H, bs), 4.33-4.23 (2H, m), 4.19-4.04(2H, m), 3.95-3.87 (1H, m), 3.79-3.63 (6H, m), 3.43-3.39 (2H, m),2.15-1.74 (4H, m), 1.35-1.19 (6H, m). LCMS [M+H]+calcd for C₁₆H₂₇N₂O₈:375.17; found: 375.19.

5-Hydroxy-2-[4-(2-hydroxyethoxy)tetrahydropyran-4-yl]-6-oxo-1,6-dihydropyrimidine-4-carboxylicacid ethyl ester. A solution of an intermediate 17 (9.3 g, 25 mmol) inxylenes (150 mL) was refluxed for 18 h. After cooling to room temp, themixture was shaken with 0.2 M Na₂CO₃. The aqueous phase was washed withEtOAc, made acidic with conc'd HCl and extracted with CH₂Cl₂. Theorganic phase was dried (Na₂SO₄) and concentrated. The resulting residuewas triturated with ether to give the intermediate 18 as a brown solid(0.87 g, 10% yield) and impure product (2.36 g). LCMS [M+H]⁺ calcd forC₁₄H₂₁N₂O₇: 329.13; found: 329.15.

A solution of intermediate 18 (0.86 g, 2.6 mmol) in THF (10 mL) wascooled to 0° C. Added to this was methanesulfonyl chloride (0.613 mL,7.9 mmol) followed by slow addition of triethylamine (1.07 mL, 7.9mmol). The mixture stirred for 4 h while gradually warming to room temp.before diluting with EtOAc. The mixture was washed with water and brineand dried (Na₂SO₄) before concentrating to give a dark oil. This wasdissolved in EtOH (20 mL) and THF (10 mL) and added potassium carbonate(0.56 g, 4.04 mmol). The mixture was stirred at room temp for 18 h,diluted with EtOAc (200 mL) and the solids were removed by filtration.The solution was concentrated and the residue was triturated withmethanol. Filtration gave the intermediate 19 as a white solid (0.23 g,23%). ¹H-NMR (300 MHz, CDCl₃) δ: 4.41 (2H, q, J=7.2 Hz), 4.03-3.98 (4H,m), 3.88-3.82 (2H, m), 3.74 (2H, t, J=11.2 Hz), 3.50 (3H, s), 2.44 (2H,dt, J=13.1, 4.9 Hz), 1.76 (2H, d, J=13.9 Hz), 1.38 (3H, t, J=7.1 Hz).LCMS [M+H]⁺ calcd for C₁₅H₂₁N₂O₈S₃: 389.10; found: 389.13.

1-Hydroxycyclobutanecarbonitrile. To a flask containing cyclobutanone(13.41 g, 191 mmol) was added a solution of potassium phosphatemonobasic (29.10 g, 214 mmol) in water (50 mL), followed by a solutionof sodium cyanide (10.39 g, 210 mmol) in water (50 mL), and the reactionwas stirred for 16 hours. The reaction was treated with diethyl ether(100 mL) and stirred for 30 minutes. The separated aqueous layer waswashed with ether (2×100 mL), and the combined extracts wereconcentrated to an oil. The oil was dissolved in dichloromethane, dried(sodium sulfate), filtered, and concentrated to give an amber oil (15.10g), which contained approximately 15% of intermediate 20. Theintermediate was used without further purification or treatment. ¹H NMR(500 MHz, CDCl₃) δ: 3.15 (1H, br s), 2.60-2.68 (2H, m), 2.29-2.38 (2H,m), 1.89-2.03 (2H, m).

1-(2-Chloroethoxy)cyclobutanecarbonitrile. Zinc chloride (36.03 g, 264mmol) was fused using a propane torch while under vacuum. The moltenzinc was cooled and the evacuated flask was flushed with nitrogen. Theflask was loaded with intermediate 2 (15.10 g,) and 2-chloroethanol(17.7 g, 218 mmol) and stirred with heating (90° C.) for 20 hours. Thereaction mixture was diluted with water (200 mL) and extracted withethyl acetate (1×150 mL, 4×100 mL). The combined organic layers weredried (sodium sulfate), filtered, and concentrated to an oil in-vacuo.The crude product was purified by vacuum distillation (b.p.₁₂ 85° C.) togive intermediate 21 (5.00 g, 31.3 mmol, 16.4% over two steps) as aclear liquid. ¹H NMR (500 MHz, CDCl₃) δ: 3.75 (2H, t, J=5.5 Hz), 3.65(2H, t, J=5.6 Hz), 2.52-2.61 (2H, m), 2.31-2.43 (2H, m), 1.91-2.06 (2H,m).

A solution of intermediate 21 (2.64 g, 16.5 mmol) in ethanol (10 mL) wastreated with a 50 weight-percent aqueous. solution of hydroxylamine(3.34 g, 50 mmol), and stirred with heating (60° C.) for 16 hours. Thesolvent was removed in vacuo, and the residue was dried fromethanol-water (1:1, 10 mL) twice, to give as an oily solid. This wasused immediately in the following step.

A cold (0° C.) solution of the above oily solid in ethanol (5 mL) andwater (10 mL) was treated with a solution of diethylacetylenedicarboxylate (4.22 g, 25 mmol) in ethanol (50 mL). Thereaction was stirred for 5 minutes, then warmed to room temperature, andstirred for 2 hours. The reaction was diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined extracts were dried(sodium sulfate), filtered, and concentrated in vacuo. The crude waspartially purified by flash silica gel column chromatography, elutingwith 10% to 35% ethyl acetate in hexanes. Product fractions were pooledand concentrated in vacuo to give intermediate 22 (2.58 g, 48%) as ayellow oil, which was used immediately in the following step. LC/MS[M+H]⁺=327.14.

A solution of intermediate 22 (2.51 g, 7.7 mmol) in 1,2,4-trimethylbenzene (25 mL) was heated at reflux (180° C.) for 3 hours, then cooledto room temperature. The solvent was removed in vacuo, and the crude wasdissolved in ethyl acetate (75 mL) and extracted with a saturatedaqueous solution of sodium bicarbonate (4×75 mL). The combined extractswere brought to pH 1-2 using 6N hydrochloric acid, and the resultantsolid was extracted with ethyl acetate (4×50 mL). The combined extractwas dried (sodium sulfate), filtered, and concentrated in vacuo to giveintermediate 23 (0.235 g, 5.2% over two steps) as a brown solid. ¹H NMR(500 MHz, CDCl₃) δ: 10.54 (1H, s), 4.46 (2H, q, J=7.1 Hz), 3.95-4.00(4H, m), 2.67-2.74 (2H, m), 2.30 (2H, ddd, J=12.4, 9.9, 7.3 Hz),2.09-2.19 (1H, m), 1.97-2.06 (1H, m), 1.44 (3H, t, J=7.2 Hz). LC/MS[M+H]⁺=281.11.

Alternative preparation of intermediate 23 from cyclobutanone.

5,8-Dioxa-spiro[3.4]octane. A solution of cyclobutanone (7.7 g, 0.11mol), ethylene glycol (6.82 g, 0.1 1 mol) and p-toluenesulfonic acidmono hydrate (200 mg, 1 mmol) in benzene (200 mL) was heated at refluxwith a Dean-Stark trap for 14 hrs. After cooling, the mixture was washedwith aqueous sodium bicarbonate solution (saturated, 15 mL), then withbrine and dried (magnesium sulfate), filtered and concentrated to obtain9.37 g (82%) of intermediate 24 as a colorless liquid: ¹H NMR (CDCl₃,500 MHz) δppm 3.87 (4H, s, CH₂), 2.31 (4H, t, J=8 Hz, CH₂), 1.67 (2H,qt, J=8 Hz, CH₂); ¹³C NMR (CDCl₃, 125.77 Hz) δ: 109.08 (C), 63.87 (CH₂),35.58 (CH₂), 11.42 (CH₂).

2-{[1-(2-hydroxyethoxy)cyclobutanecarboximidoyl]-aminooxy}but-2-enedioicacid diethyl ester. To a mixture of intermediate 24 (5.70 g, 50 mmol)and trimethylsilyl cyanide (5.05 g, 50 mmol) was added a catalyticamount of ZnI₂ (12 mg) in a cool water bath of ˜10° C. and the mixturestirred at room temperature for 5 hrs to obtain 10.7 g of1-(2-trimethylsilanyloxyethoxy)cyclobutanecarbonitrile as a mobile oil:¹H NMR (CDCl₃, 500 MHz) δ: 3.75 (2H, t, J=5 Hz, OCH₂), 3.55 (2H, t, J=5Hz, OCH₂), 2.51-2.56 (2H, m, CH₂), 2.30-2.37 (2H, m, CH₂), 1.91-1.98(2H, m, CH₂), 0.124 (9H, s, SiCH₃); ¹³C NMR (CDCl₃, 125.77 Hz) δppm120.43 (CN), 72.05 (C), 67.71 (CH₂), 61.49 (CH₂), 34.02 (CH₂), 12.91(CH₂), −0.29 (CH₃). LC/MS m/z 142 (M+H—SiMe₃).

A solution of 1-(2-trimethylsilanyloxyethoxy)cyclobutanecarbonitrile(3.5 g, 16.4 mmol) and 50% aqueous hydroxylamine (1.08 g, 16.4 mmol) inEtOH (16 mL) was stirred in an oil bath heated at 80° C. for 2.5 hrs andthen cooled to room temperature. To a solution was added drop-wisediethyl acetylenedicarboxylate (2.93 g, 17.2 mmol) in an ice-bath andthe mixture stirred at room temperature for 5 hrs. This mixture wasconcentrated in vacuo to obtain 6.16 g of a crude brownish oilcontaining intermediate 25: ¹H NMR (500 MHz, CDCl₃) δ: 1.19-1.38 (6 H,m) 1.72-1.86 (2 H, m) 2.06-2.24 (2 H, m) 2.29-2.49 (2 H, m) 3.26-3.38 (2H, m) 3.65-3.76 (2H, m) 4.11-4.19(2 H, m) 4.24-4.38(2 H, m) 5.67(0.25 H,s) 5.85 (0.5 H, s). HRMS (M+H) calcd for C₁₅H₂₅N₂O₇ 345.1662, found345.1648.

5-hydroxy-2-[-1-(2-hydroxy-ethoxy)-cyclobutyl]-6-oxo-1,6-dihydro-pyrimidine-4-carboxylicacid ethyl ester. A solution of a crude intermediate 25 (5.9 g) inxylenes (30 mL) was heated at 150-155° C. for 20 h. The mixture wasconcentrated in vacuo and the residue re-dissolved in EtOAc (30 mL) wasextracted with 1M aq. sodium carbonate solution (3×20 mL). The aqueousextracts were acidified with careful addition of concentrated HCl, andthis mixture was extracted with CH₂Cl₂ (2×20 ml). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated to obtainintermediate 26 (1.19 g, 24% over three steps) as brownish oil: LC/MSm/z 299 (M+H).

Ethyl1-(methylsulfonyl)-5-(methylsulfonyloxy)-2-(1-(2-(methylsulfonyloxy)ethoxy)cyclobutyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate(27): A cold (0° C.) solution of intermediate 26 (7.23 g, 25 mmol) inanhydrous tetrahydrofuran was treated with methanesulfonylchloride(Aldrich) by dropwise addition. The solution was warmed to roomtemperature and stirred for 4 hrs. The reaction was concentratedin-vacuo, and the crude product was dissolved in ethyl acetate (75 mL)and washed with saturated sodium bicarbonate solution. The organicsolution was dried (sodium sulfate), filtered to remove solids, andconcentrated in vacuo to give intermediate 27 as a brown oil. This wasused in the subsequent reaction without further purification. ¹H NMR(500 MHz, CDCl₃) δ: 4.49 (2H, q, J=7.0 Hz), 4.35-4.38 (2H, m), 3.93-4.00(1H, m), 3.66-3.67 (3H, s), 3.62-3.65 (2H, m), 3.44-3.46 (3H, s),3.05-3.07 (3H, s), 2.74-2.82 (1H, m), 2.60-2.67 (2H, m), 2.41-2.49 (2H,m), 1.43 (3H, t, J=7.0 Hz). LCMS (M+H): 532.94.

To a solution of intermediate 27 obtained above in absolute ethanol (50mL) and anhydrous tetrahydrofuran (75 mL) was added anhydrous potassiumcarbonate (3.46 g, 25 mmol), and the reaction was stirred with heating(65° C.) for 20 hrs. Solvent was removed in-vacuo and the crude productwas dissolved in water (150 mL) and extracted with ethyl acetate (2×100mL). The aqueous layer was made acidic (pH 1-2) using 6.0 N hydrochloricacid, and the resulting solid was extracted with ethyl acetate (2×75mL). The combined extract was dried (sodium sulfate), filtered to removesolids, and concentrated to give intermediate 28 (4.30 g, 61%) as alight brown solid. ¹H NMR (500 MHz, CDCl₃) δ: 10.57 (1H, s), 4.46 (2H,q, J=7.2 Hz), 3.97 (4H, s), 2.67-2.73 (2H, m), 2.27-2.33 (2H, m),2.10-2.18 (1H, m), 1.98-2.06 (1H, m), 1.44 (3H, t, J=7.2 Hz). ¹³C NMR(126 MHz, CDCl₃) δ: 169.56, 157.68, 150.41, 148.19, 125.24, 79.09,62.63, 58.52, 42.66, 34.72, 14.18, 13.87; LC/MS (M+H): 281.13.

Intermediate 29 was prepared (50% yield) according to the procedure forintermediate 24. ¹H NMR (500 MHz, C₆D₆) δ: 3.49 (4H, t, J=5.5 Hz), 2.23(4H, t, J=8 Hz), 1.63 (2H, qt, J=8 Hz), 1.24 (2H, qt, J=5.5 Hz).

Intermediate 30 was prepared (52% yield) according to the procedure forintermediate 25. ¹H NMR (500 MHz, C₆D₆) δ: 3.54 (2H, t, J=6.1 Hz), 3.45(2H, t, J=6.1 Hz), 2.06-2.12 (2H, m), 1.87 (2H, dq, J=9.7, 2.6 Hz), 1.68(2H, qt, J=6.1 Hz), 1.43-1.51 (1H, m), 1.26-1.34 (1H, m), 0.10 (9H, s).LC/MS [M+H]⁺=359.20

Intermediate 31 was prepared (69% yield) according to the procedure forintermediate 26. ¹H NMR (500 MHz, CDCl₃) δ: 4.46 (2H, q, J=7.0 Hz), 3.84(2H, t, J=5.5 Hz), 3.41 (2H, t, J=5.5 Hz), 2.51-2.58 (2H, m), 2.29-2.38(2H, m), 1.89-1.99 (2H, m), 1.82-1.90 (3H, m), 1.45-(3H, t, J=7.0 Hz),1.31-1.41 (1H, m). LC/MS (ESI) [M+H]⁺=313.05.

A cold (0° C.) solution of intermediate 31 (3.0 g, 9.6 mmol) intetrahydrofuran (25 mL) was treated with methanesulfony chloride (3.30g, 29 mmol) followed by dropwise addition of triethylamine (4.7 mL, 33.6mmol). The reaction was stirred for 16 hours at room temperature. Thesolvent was removed in vacuo and the mixture was dissolved in ethanol(50 mL) and dimethylformamide (25 mL). To the slurry was added potassiumcarbonate (1.36 g, 9.7 mmol) and the reaction was stirred at roomtemperature for 16 hours, followed by heating (80° C.) for 3 hours. Thesolvent was removed in vacuo. The crude product was diluted with ethylacetate (50 mL) and washed with IN hydrochloric acid (2×50 mL),extracted with ethyl acetate (2×25 mL) then brine ((50 mL). The solutionwas then dried (sodium sulfate), filtered and concentrated to giveintermediate 32 (0.534 g, 19%) as a brown solid. ¹H NMR (500 MHz, CDCl₃)δ: 10.64 (1H, br s), 4.45 (2H, q, J=7.0 Hz), 4.38 (2H, br), 3.91 (2H, t,J=5.0 Hz), 2.81 (2H, br), 2.36-2.44 (2H, m), 1.87-1.97 (1H, m),1.82-1.86 (2H, m), 1.67-1.75 (1H, m), 1.43 (3H, t, J=7.2 Hz).

4-Fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile (33) and4-(1H-1,2,4-triazol-1-yl)-2-fluorobenzonitrile. To a solution of2,4-difluorobenzonitrile (10 g, 72 mmol) dissolved in THF (20 mL), andDMF (40 mL) was added 1,2,4-triazole sodium derivative (6.3 g, 70 mmol)and the mixture was stirred at 90° C. for 3 h, filtered andconcentrated. The residue was adsorbed onto Silica gel and purified byflash chromatography eluting with 0%-10%-30% EtOAc/hexanes to giveintermediate 33 as colorless needles (2.46 g, 18%) and intermediate 34was obtained as a white solid (0.7455 g, 6%).

Intermediate 33: ¹H NMR (500 MHz, CDCl₃) δ: 8.89 (1H, s), 8.19 (1H, s),7.85 (1H, dd, J=8.7, 5.6 Hz), 7.60 (1H, dd, J=8.8, 2.4 Hz), 7.28-7.24(1H, m). LCMS (M+H) calcd for C₉H₆N₄F: 189.05; found: 189.13.

Intermediate 34: ¹H NMR (500 MHz, CDCl₃) δ: 8.66 (1H, s), 8.15 (1H, s),7.79 (1H, dd, J=8.5, 6.7 Hz), 7.69 (1H, dd, J=9.5, 1.8 Hz), 7.65-7.63(1H, m). LCMS (M+H) calcd for C₉H₆N₄F: 189.05; found: 189.13.

(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride.Nitrile 33 (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL).Aqueous HCl (15 mL, 1N) was added followed by 10% Pd/C (200 mg). Themixture was shaken under H₂ at 55 psi for 4 h., filtered over celite andconcentrated. The residue was partitioned between EtOAc and water. Theaqueous phase was lyophilized to give intermediate 35 as a white powder(2.96 g, 99%). ¹H NMR (500 MHz, CD₃OD) δ: 9.51 (1H, s), 8.63 (1H, s),7.85 (1H, dd, J=8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 7.49 (1H,td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd for C₉H₁₀N₄F: 193.08;found: 193.16.

(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride.Intermediate 36 was prepared (79% yield) following the procedure forintermediate 35 using intermediate 34. ¹H NMR (500 MHz, CD₃OD) δ: 9.25(1 H, s), 8.46 (1H, s), 7.80 (1H, dd, J=8.6, 5.8 Hz), 7.64 (1H, dd,J=8.8, 2.4 Hz), 7.44 (1H, td, J=8.3, 2.6 Hz), 4.17 (2H, s). LCMS (M+H)calcd for C₉H₁₀N₄F: 193.08; found: 193.16.

4-Fluoro-2-methylsulfanyl-benzylamine.4-Fluoro-2-(methylthio)benzonitrile (prepared as in Anthony, N. J. etal. PCT Appl. WO 02/30931, 2002) (1.67 g, 0.1 mol) was dissolved in 20mL THF and under N₂ treated with 10 mL 2M BH₃.Me₂S. This was heated at60° C. for 2 hrs. Heating was discontinued and 5 mL MeOH was cautiouslyadded, followed by the cautious addition of 4 mL 6N HCl. Then 20 mL moreH₂O added and EtOAc and the layers were separated. The aqueous layer wasmade basic with IN NaOH and extracted with CH₂Cl₂. The extracts weredried (MgSO₄), filtered, concentrated and dried in vacuum to giveintermediate 37 (1.3 g, 76%) as a solid. ¹H NMR (500 MHz, CDCl₃) δ:7.20-7.31 (1 H, m) 6.90 (1 H, dd, J=2.4 Hz) 6.75-6.86 (1 H, m) 3.86 (2H, s) 2.47 (3 H, s). LC/MS (M+H): 172.

N-t-Butoxycarbonyl-(4-fluoro-2-(methylthio)phenyl)methanamine. A stirredsolution of intermediate 37 (5.1 g, 0.03 mol) and 3.3 g triethylamine in100 mL CH₂Cl₂ under N2 was treated with di-t-butyl dicarbonate (7.2 g,0.033 mol) portionwise and stirred at room temperature for 30 min. Then,the reaction mixture was washed with dil HCl and water. The organiclayer was dried over MgSO₄, filtered and concentrated to leave 8.1 g(100%) of intermediate 38 as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ:7.22-7.29 (1 H, m) 6.89 (1 H, dd, J=9.61, 2.29 Hz) 6.75-6.83 (1H, m)4.93 (1 H, s) 4.31 (2 H, d, J=5.49 Hz) 2.47 (3 H, s) 1.44 (9 H, s).LC/MS (M+H): 272.

(4-Fluoro-2-(methylsulfonyl)phenyl)methanamine hydrochloride. A solutionof intermediate 38 (8.1 g, 0.03 mol) in 100 mL acetone and 50 mL waterwas treated with oxone (18.5 g, 0.03 mol) and stirred for 10 min. Thenan additional 18.5 g oxone was added and the mixture was warmed at 60°C. for 1.5 hrs. This was cooled, concentrated to remove acetone andextracted with CH₂Cl₂. This was concentrated to an oil, dissolved in 20mL ethanol and treated with 10 mL 6N HCl and warmed at 60° C. for 2 h.Removal of solvents gave a gum which was crystallized from ethanol togive intermediate 39 (2.0 g) as crystals. The aqueous layer was madebasic with ammonium hydroxide and extracted further with CH₂Cl₂ andconcentration of the extracts gave a gum which was treated with HCl inethanol to give an additional 0.9 g of intermediate 39. ¹H NMR (500 MHz,DMSO-D₆) δ: 8.54 (3 H, s) 7.89 (1 H, dd, J=8.54, 5.19 Hz) 7.67-7.85 (2H, m) 4.40 (2 H, s) 3.41 (3 H, s). LC/MS (M+H)=204.

5-Fluoro-2,N,N-trimethyl-benzenesulfonamide. To a solution of5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in THF (25mL) was added drop-wise in 15 min a solution of dimethylamine in THF(2M, 25 mL, 50 mmol) under nitrogen and the mixture stirred for 5 min.The insoluble materials formed were filtered and the filtrateconcentrated. The residue was purified by column chromatography (SiO₂,5% Et₂O in CH₂Cl₂) to obtain intermediate 40 (4.3 g, 90%) as a clearoil. ¹HNMR (500 MHz, CDCl₃) δ: 2.57 (3 H, s) 2.82 (3 H, s) 2.82 (3 H, s)7.12-7.18 (1 H, m) 7.28 (1 H, dd, J=8.2, 5.5 Hz) 7.59 (1 H, dd, J=8.2,2.1 Hz). LC/MC (M+H): 218.

2-Bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide. A mixture ofintermediate 40 (435 mg, 2.0 mmol) and N-bromosuccinimide (391 mg, 2.2mmol) in CCl₄ (20 mL) was stirred in an oil bath heated at 80-90° C.under nitrogen for 5 min. To this mixture was added2,2′-azobisisobutyronitrile (AIBN,100 mg) and the mixture continued toheat at 80-90° C. for 30 min. After cooling, the insoluble precipitateswere filtered and the filtrate concentrated and purified by columnchromatography (SiO₂, CH₂Cl₂) to obtain intermediate 41 (440 mg, 74%).¹HNMR (500 MHz, CDCl₃) δ: 2.87 (6 H, s) 4.86 (2 H, s) 7.28 (1 H, dd,J=8.55, 2.75 Hz) 7.61-7.65 (2 H, m). LC/MC (M+H): 296/298.

2-Azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide. A mixture ofintermediate 41 (880 mg, 2.97 mmol) and sodium azide (200 mg, 3 mmol) inDMF (4 mL) was stirred under nitrogen in an oil bath heated at 55-60° C.for 30 min and the solvent was removed in vacuo. The residue waspartitioned between CH₂Cl₂ and water, and the organic phase was washedwith water, dried (Na₂SO₄), filtered and concentrated to obtainintermediate 42 (670 mg, 87%) of as a yellow oil. ¹HNMR (500 MHz, CDCl₃)δ: 2.84 (6 H, s) 4.78 (2 H, s) 7.29-7.34 (1 H, m) 7.59-7.64 (2 H, m).

2-(aminomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide hydrochloride.To a solution of intermediate 42 (660 mg, 2.6 mmol) in THF (10 mL) andwater (2 mL) was added triphenylphosphine (740 mg, 2.8 mmol), and themixture stirred under nitrogen for 1 h. The THF was evaporated in vacuoand a mixture of the residue and 6N HCl (3 mL) in MeOH (5 mL) was heatedin an oil bath at 80° C. for 20 h. This was washed with CH₂Cl₂, and theaqueous phase basified with dilute NH₄OH and extracted with CH₂Cl₂. Theorganic extract was dried (Na₂SO₄), filtered and concentrated to obtainfree amine 43 (210 mg, 35%) as an oil. ¹H NMR (500 MHz, CDCl₃) δ: 2.84(6 H, s) 4.10 (2 H, s) 7.23-7.29 (1 H, m) 7.53-7.60 (2 H, m); LC/MS(M+H): 233.

Alternatively, a solution of intermediate 42 (23.6 g, 91.37 mmOl) inEtOH (100 mL) and 5M aq. HCl (22 mL) was degassed by bubbling N2 throughit for 5 min. and 10%Pd/carbon (2.0 g) was added. This mixture wasevacuated and vented to H₂ (repeated three times) and left on Parrshaker for 20 h under H2 (40 psi) atmosphere. The reaction mixture wasfiltered, concentrated and resulting residue was taken up in water (200mL). This was extracted with EtOAc (3×50 mL). The organic layerdiscarded and aqueous layer freeze dried to afford 43 (16.3 g, 66%) aspale yellow powder.

To a solution of intermediate 28 (0.103 g, 0.367 mmol) in anhydrousdimethylformamide (4 mL) was added anhydrous potassium carbonate (0.206g, 1.47 mmol) and benzyl bromide (0.071 g, 0.39 mmol), and the reactionwas stirred with heating (60° C.) for 18 hours under nitrogenatmosphere. To the reaction mixture was added lithium hydroxide (0.024g, 0.92 mmol), water (5 mL) and ethanol (5 mL). The reaction was stirred(60° C.) for 2 hours, after which HPLC indicated reaction was complete.The solvent was removed in vacuo, and the crude product was dissolved inwater (˜10 mL) and brought to pH 1-2 using 6 N hydrochloric acid. Theproduct was extracted with ethyl acetate (3×30 mL), dried (Na₂SO₄),filtered and concentrated to give 0.13 g (100%) of intermediate 44 as anoil which solidified upon standing. The intermediate was used in thefollowing reaction without further purification: ¹H NMR (500 MHz, CDCl₃)δ: 7.54 (2H, d, J=7.3 Hz), 7.30-7.38 (3H, m), 5.49 (2H, s), 3.95-4.01(4H, m), 2.67-2.74 (2H, m), 2.33-2.41 (2H, m), 2.06-2.14 (2H, m).

To a solution of intermediate 44 (obtained above) in dimethylformamide(3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 0.167 g, 0.44 mmol) and the mixture wasstirred for 20 minutes. To this was added2-(aminomethyl)-5-fluoro-N-methylbenzamide hydrochloride (preparedaccording to M. Egbertson et al PCT Appl. WO 03077850) andN,N-dimethylaminopyridine (0.068 g, 0.55 mmol) and the reaction wasstirred for 16 hours. The solvent was removed in vacuo and the crudeproduct in ethyl acetate (25 mL) was washed with 1.0 N hydrochloric acid(25 mL), then dried (Na₂SO₄), filtered, and concentrated to give anorange-brown solid. This was purified by flash silica gel columnchromatography, eluting with 30% to 60% ethyl acetate in hexanes, togive a colorless oil. The oil was triturated with diethyl ether anddried in-vacuo to give intermediate 45 (0.101 g, 54% over two steps) asa white glassy solid: ¹H NMR (500 MHz, CDCl₃) δ: 8.62 (1H, t, J=6.1 Hz),7.44-7.51 (3H, m), 7.27-7.33 (3H, m), 7.13 (1H, dd, J-8.9, 2.7 Hz), 7.08(1 H, dt, J=8.2, 2.7 Hz), 6.49-6.58 (1H, m), 5.28 (2H, s), 4.56 (2H, d,J=6.4 Hz), 3.90-4.00 (4H, m), 2.98 (3H, d, J=4.9 Hz), 2.71-2.79 (2H, m),2.26-2.36 (2H, m), 2.14-2.24 (1H, m), 2.04-2.11 (1H, m). LC/MS (M+H)507.13.

2-(1H-1,2,4-triazol-1-yl)benzonitrile: A suspension of2-fluorobenzylnitrile (3.0 g, 25 mmol) and 1,2,4-triazole sodium complex(2.4 g, 27 mmol) were stirred in THF (7 mL) and DMF (14 mL) at 95° C.for 18 h. After cooling and concentrating, the product was crystallizedfrom hot CH₂Cl₂/hexane (1:1) to give the title compound as a white solid(4.25 g, 100% yield). ¹H-NMR (300 MHz, CDCl₃) δ: 8.74 (1H, s), 8.16 (1H,s), 7.82 (1H, dd, J=4.9,1.3 Hz), 7.77-7.25 (2H, m), 7.57-7.51 (1H, m).LCMS [M+H]⁺ calcd for C₉H₇N₄: 171.06; found: 171.12.

2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride: Intermediate46 (4.25 g, 25 mmol) was dissolved in EtOH (50 mL) and 1N HCl (25 mL).Added Pd/C (1 g) and mixture was shaken under H₂ for 2 h at 50 psi.After filtration over celite and concentration, the residue wastriturated with diethyl ether and the title compound was collected as awhite solid (3.94 g, 75% yield). ¹H-NMR (300 MHz, CD₃OD) δ: 9.01 (1H,s), 8.32 (1H, s), 7.78-7.64 (4H, m), 4.15 (2H, s). LCMS [M+H]⁺ calcd forC₉H₁₁N₄: 175.09; found: 175.17.

4-Fluoro-2(2H-1,2,3-triazol-2-yl)benzonitrile: To a solution of1H-1,2,3-triazole (3.5 g, 50.7 mmol) in THF (10 mL) and DMF (20 mL) wasadded portionwise, NaH (1.3 g, 51 mmol, 95%). The mixture was stirred atroom temp for 30 min. Added to this was 2,4-difluorobenzonitrile (7.6 g,55 mmol) and the mixture was stirred at 85° C. for 3 h. The whitemixture was concentrated and purified by flash chromatography elutingwith 0%-5%-10% EtOAc/hexane to give the title compound as white needles(0.34 g, 3% yield). ¹H-NMR (300 MHz, CDCl₃) δ: 7.92 (2H, s), 7.88-7.79(2H, m), 7.19-7.12 (1H, m). LCMS [M+H]⁺ calcd for C₉H₆N₄F: 189.05;found: 189.12.

4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanamine hydrochloride:Intermediate 48 (0.34 g, 1.8 mmol) was dissolved in EtOH (50 mL). Addedto this solution was 1N HCl (10 mL) and catalytic Pd/C. The mixture wasshaken under H₂ at 55 psi for 4 h, filtered over celite and concentratedto give the title compound as a yellow solid (0.4021 g, 98% yield).¹H-NMR (500 MHz, CD₃OD) δ: 8.13 (2H, s), 7.87 (1H, dd, J=4.9, 2.6 Hz),7.73 (1H, dd, J=4.9, 2.6 Hz), 7.34 (1H, td, J=8.2, 2.7 Hz), 4.35 (2H,s). LCMS [M+H]⁺ calcd for C₉H₁₀N₄F: 193.08; found: 193.16.

2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benonitrile: Added to a solution of1,1-dioxo[1,2]thiazinane (3.37 g, 25 mmol) in DMF (35 mL) was sodiumhydride (0.675 g, 25 mmol, 95%) and the mixture was stirred at room tempfor 15 min. 2-Fluorobenzonitrile (3.37 mL, 31.3 mmol) was added and themixture was stirred at 80° C. for 18 h. The mixture was cooled, dilutedwith water and extracted with EtOAc. The organic phase was washed withwater and brine, dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography eluting with 10%-100% EtOAc/hexane. Theisolated solid was recrystalized from hot EtOAc/hexane (2:1) to give thetitle compound as white crystals (4.15 g, 70% yield). 1H-NMR (300 MHz,CDCl₃) δ: 7.70 (1H, dd, J=7.7,1.1 Hz), 7.64-7.53 (2H, m), 7.41 (1H, td,J=7.3, 1.6 Hz), 3.72 (2H, t, J=5.5 Hz), 3.32 (2H, t, J=6.0 Hz),2.40-2.32 (2H, m), 2.05-1.97 (2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₂N₂O₂S:237.06; found: 237.10.

2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzylamine hydrochloride:Intermediate 50 (2.63 g, 11.14 mmol) was dissolved in EtOH (150 mL) and1N HCl (13 mL). Added to this was Pd/C (0.5 g) and the mixture wasshaken under H₂ at 55 psi for 24 h. Filtration over celite andconcentration gave the title compound as a white solid (2.93 g, 95%yield). ¹H-NMR (300 MHz, CD₃OD) δ: 7.61-7.47 (4H, m), 4.30 (2H, q,J=13.7 Hz), 3.96-3.87 (1H, m), 3.49-3.36 (3H, m), 2.40-2.31 (2H, m),2.05-1.96 (2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₇N₂SO₂: 241.10; found:241.10.

4-Fluoro-2-(1,1-dioxo-1 λ6-[1,2]thiazinan-2-yl)benzonitrile: To asolution of 1,1-dioxo[1,2]thiazinane (8.84 g, 65.4 mmol) in DMF (20 mL)and THF (10 mL) was added portion-wise sodium hydride (1.65 g, 65.5mmol, 95%). After stirring for 30 min, 2,4-difluorobenzonitrile (10.0 g,72 mmol) was added and the mixture was stirred at 90° C. for 2.5 h. Themixture was cooled and concentrated and the residue was purified byflash chromatography eluting with 0%-10% EtOAc/hexane to give the titlecompound as white needles (1.37 g, 8% yield). ¹H-NMR (500 MHz, CDCl₃) δ:7.70 (1H, dd, J=8.8, 5.8 Hz), 7.30 (1H, dd, J=8.8, 2.4 Hz), 7.15-7.12(1H, m), 3.72 (2H, t, J=5.3 Hz), 3.33 (2H, t, J=6.1 Hz), 2.40-2.35 (2H,m), 2.05-2.01 (2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₂N₂FO₂S: 255.06;found: 255.19.

4-Fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzylamine hydrochloride:Following the procedure for Intermediate 51 using Intermediate 52 (1.37g, 5.4 mmol) gave the title compound as a white solid (1.58 g, 100%yield). ¹H-NMR (300 MHz, CD₃OD) δ: 7.61 (1H, dd, J=8.4, 6.2 Hz), 7.38(1H, dd, J=9.3, 2.7 Hz), 7.28 (1H, td, J=8.2, 2.7 Hz), 7.26 (2H, dd,J=21.4, 13.7 Hz), 3.93-3.84 (1H, m), 3.50-3.41 (3H, m), 2.40-2.31 (2H,m), 2.04-1.96 (2H, m). LCMS [M+H]⁺ calcd for C₁₁H₁₆N₂FO₂S: 259.09;found: 259.24.

To a solution of 1-(2-chloroethyl)cyclopentanecarbonitrile (1.38 g, 8.73mmol; prepared according to R. M. Burk et al Heterocycles 1993, 35, 205)in 40 mL MeOH was added 1 mmol sodium iodide and the solution wassaturated with ammonia. The reaction bottle was sealed and warmed at 90°C. with stirring for 20 h. After cooling the reaction bottle was openedand solvents were evaporated under vacuum. LC/MS (M+H): 139. ¹H NMR (500MHz, CDCl₃) δ: 1.50-2.33 (10H, m), 3.53-3.78 (2H, m).

To a solution of diethyl-2-(benzyloxy)-3-hydroxyfumarate [prepared frombenzyloxy ethylacetate (2.91 g, 0.015 mol) and diethyloxalate (2.19 g,0.015 mol) with an equivalent amount of sodium hydride in 40 mL THF and2 drops EtOH by stirring for 30 min] in 20 mL EtOH was addedintermediate 54 in 10 mL EtOH and with stirring 60% NaH (300 mg, 0.0075mol) was added portionwise. This was stirred for 3 h at rt andconcentrated. The residue was dissolved in CH₂Cl₂ and washed with water.The CH2Cl2 layer was dried over MgSO₄, filtered and concentrated.Chromatography on silica and elution with 9:1 CH₂Cl₂:Et₂O gave 600 mg ofthe title compound 55 (Yield=19%). LC/MS (M+H): 369. ¹H NMR (500 MHz,CDCl₃) δ: 1.29 (3H, t, J=7.2 Hz), 1.56 (1H, s), 1.68-1.80 (3H, m),1.85-1.96 (1H, m) 2.04-2.17 (3H, m), 4.03-4.08 (1H, m), 4.03-4.10 (2H,m), 4.22 (1H, q, J=7.0 Hz), 4.32 (1H, q, J=7.0 Hz), 4.63 (1H, s), 5.24(2H, s), 7.28-7.40 (3H, m), 7.47 (2H, d, J=6.7 Hz).

Intermediate 55 was dissolved in 15 mL TFA and stirred at rt for 16 h.The TFA was removed and the crude chromatographed on C1 8 using 10%CH₃CN/H₂O initially as eluant. Product eluted with 20% CH₃CN. Purefractions were concentrated and extracted with CH₂Cl₂. Evaporation ofthe solvent left 300 mg (Yield=51%) of the title compound 56. LC/MS(M+H): 279. ¹H NMR (300 MHz, CDCl₃) δ: 1.41 (3H, t, J=7.1 Hz), 1.65-1.79(4H, m), 1.84-1.97 (2H, m), 2.00-2.12 (4H, m), 3.98-4.08 (2H, m), 4.44(2H, q, J=7.0 Hz), 10.78 (1H, s).

To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (10.0 g, 70 mmol) andtriethylamine (20 mL, 142 mmol) in diethylether (50 mL) cooled to 0° C.was added dropwise tosyl chloride (13.5 g, 71 mmol) dissolved in CH₂Cl₂.The resulting suspension was stirred at room temperature 5 h. and washedwith saturated aqueous NaHCO₃, water and dried (Na₂SO₄). Concentrationgave the Intermediate 57 as a white solid (20.20 g, 97%). ¹H-NMR (300MHz, CDCl₃) δ: 7.61 (2H, d, J=8.0 Hz), 7.28 (2H, d, J=8.0 Hz), 3.86 (4H,s), 3.11 (4H, t, J=5.8 Hz), 2.40 (3H, s), 1.75 (4H, t, J=5.8 Hz). LCMS(M+H) calcd for C₁₄H₂₀NO₄S: 298.1 1; found: 298.16.

To a stirred solution of zinc iodide (2.05 g, 6.26 mmol) andIntermediate 57 (9.3 g, 31.3 mmol) in dichloromethane (10 mL) was addedtrimethylsilylcyanide (4.29 mL, 31.3 mmol) with water bath cooling. Theresulting mixture was stirred at room temp for 2 h and concentrated. Theamber oil was used in the next step without purification.

To solution of above crude in EtOH (60 mL) was added hydroxylamine (2.1mL, 31.3 mmol, 50wt % in water) and the resulting mixture was stirred atroom temperature. After 18 h diethylacetylenedicarboxylate (6.0 mL, 37.5mmol) was added and stirred for additional 3 days and concentrated. Theresidue was purified by flash chromatography eluting with 0%-25%-50%EtOAc/Hexane to give the Intermediate 58 as a yellow foam (11.72 g,71%). ¹H-NMR (300 MHz, CDCl₃) δ: 7.62 (2H, t, J=7.7 Hz), 7.30 (2H, t,J=8.2, 2.0 Hz), 5.27 (1H, s), 4.34-4.23 (2H, m), 4.19-4.05 (2H, m),3.68-3.66 (2H, m), 3.54-3.49 (2H, m), 3.34-3.28 (2H, m), 2.72 (1H, dt,J=11.4, 2.5 Hz), 2.66-2.57 (1H, m), 2.40 (3H, d, J=1.6 Hz), 2.05-1.89(4H, m), 1.35-1.22 (6H, m). LCMS (M+H) calcd for C₂₃H₃₄N₃O₉S: 528.20;found: 528.13.

1,2,4-trimethylbenzene (100 mL) was added to Intermediate 58 (11.7 g, 22mmol) and the mixture was stirred at 140° C. for 3 h. The mixture wascooled to room temp and concentrated. Residue dissolved in CH₂Cl₂ andinsoluble solids removed by filtration and discarded. Concentration gavethe Intermediate 59 as a brown foam (5.02 g, 47% yield). LCMS (M+H)calcd for C₂₁H₂₈N₃O₈S: 482.16; found: 482.11.

A solution of Intermediate 59 (3.0 g, 6.2 mmol) and triethylamine (2.5mL, 18.7 mmol) in CH₂Cl₂ (8 mL) was cooled to 0° C. To this was added tomethanesulfonylchloride (0.47 mL), 6.3 mmol) and the resulting mixturewas stirred while gradually warming to room temperature for 18 h. Themixture was washed with water and the organic phase was dried (Na₂SO₄)to give a brown foam that was purified by flash chromatography elutingwith 10%-50% EtOAc/hexane to give the Intermediate 60 as a yellow foam(0.477 g, 14% yield). ¹H-NMR (300 MHz, CDCl₃) δ: 7.63 (2H, d, J=8.4 Hz),7.31 (2H, d, J=8.0 Hz), 4.41 (2H, q, J=7.3 Hz), 3.92-3.89 (2H, m),3.73-3.68 (1H, m), 3.49 (3H, s), 3.49-3.42 (1H, m), 2.63-2.48 (2H, m),2.43-2.41 (4H, m), 1.94-1.90 (2H, d, J-13.5 Hz), 1.39 (3H, t, J=7.1 Hz).LCMS (M+H) calcd for C₂₂H₂₈N₃O₉S₂: 542.12; found: 542.03.

To a stirred solution of Intermediate 60 (0.411 g, 0.76 mmol) in THF (10mL) at cooled to −78° C. was added dropwise a freshly prepared mixtureof sodium (0.42 g, 20 mmol) dissolved in Naphthaline (2.56 g, 20 mmol)and THF (20 mL) until the blue color persisted. The resulting mixturestirred an additional 1 h and was quenched with 1N HCl. The aqueouslayer was washed with EtOAc and freeze dried. The solids were purifiedby preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1%TFA), to give the Intermediate 61 as a white solid (0.024 g, 10% yield).LCMS (M+H) calcd for C₁₄H₂₀N₃O₅: 310.14; found: 310.10.

(4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride: Intermediate 62 was prepared according to procedure forintermediate 35. LCMS (M+H): 207.2.

(4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride: Intermediate 63 was prepared according to procedure forintermediate 35. LCMS (M+H): 207.2.

4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile and4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile. A solution of2,4-difluorobenzonitrile (7.07 g, 50.8 mmol) and3-methyl-1H-1,2,4-triazole (4.22 g, 50.8 mmol) in N,N-dimethylformamide(45 ml) was treated with powdered anhydrous potassium carbonate (10 g)and the resulting mixture was stirred at 22° C. for 18 h. The solid wasthen filtered and the filtrate was concentrated in vacuo. The residuewas diluted with ethyl acetate, washed with water and brine, dried overanhydrous magnesium sulfate and concentrated. The mixture containing the2 and 4-triazolyl-benzonitriles was purified by a combination ofchromatography on silica gel ( elution gradient of ethyl acetate inhexane) and on reversed phase silica gel to give 1.86 g (18% yield) ofIntermediate 64 and 0.526 g (5% yield) of Intermediate 65.

4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile white crystals(ethyl acetate-hexane); mp 117-118° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm):2.54 (3H, s, CH₃), 7.24 (1H, m, CH), 7.62 (1H, dd, J=2.5 Hz and J=9.1Hz, CH), 7.84 (1H, dd, J=5.6 Hz and J=8.6 Hz, CH), 8.82 (1H, s, CH).Anal. Calcd for C₁₀H₇FN₄: C 59.40, H 3.49, N 27.71; Found: C 59.25, H3.32, N 27.81.

4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile. white crystals(ethyl acetate-hexane); mp 120-121° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm):2.56 (3H, s, CH₃), 7.30 (1H, dd, J=2.5 Hz and J=8.1 Hz, CH), 7.39 (1H,m, CH), 7.91 (1H, dd, J=5.5 Hz and J=8.6 Hz, CH), 8.06 (1H, s, CH).Anal. Calcd for C₁₀H₇FN₄: C 59.40, H 3.49, N 27.71; Found: C 59.35, H3.70, N 27.77.

(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride salt. Hydrogenation of4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (0.680 g, 3.36mmol) gave 0.720 g (88% yield) of the title hydrochloride salt as awhite solid. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.40 (3H, s, CH₃), 4.02(2H, m, NCH₂), 7.50 (1H, m, CH), 7.62 (1H, dd, J=2.8 Hz and J=9.3Hz,CH), 7.84 (1H, dd, J=6.1 Hz and J=9.1 Hz, CH), 9.00 (1H, s, CH). HRMS(ESI⁺) calculated for C₁₀H₁₂FN₄ [M+H⁺]: 207.1046; found: 207.1047.

(4-Fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanaminehydrochloride salt. Hydrogenation of4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (0.244 g, 1.20mmol) gave 0.290 g (100% yield) of the title hydrochloride salt as awhite solid. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.42 (3H, s, CH₃), 3.78(2H, m, NCH₂), 7.58 (1H, m, CH), 7.67 (1H, dd, J=2.8 Hz and J=9.3 Hz,CH), 7.90 (1H, dd, J=6.0 Hz and J=8.6 Hz, CH), 8.22 (1H, s, CH). HRMS(ESI⁺) calculated for C₁₀H₁₂FN₄ [M+H⁺]: 207.1046; found: 207.1041.

2-Azido-1-bromo-4-fluorobenzene. 2-Bromo-5-fluoro aniline (2.00 g, 10.53mmol) was dissolved in concentrated HCl (10 mL) and water (10 mL) andcooled to 0° C. Aqueous NaNO₂ solution (1.09 g, 15.8 mmol of NaNO₂ in 10mL of water) was added dropwise at such a rate that the temperature didnot exceed 5° C. This mixture was stirred at 0° C. for 1.5 h. A solutionof NaN₃ (1.027 g, 15.8 mmol) and NaOAc (12.95 g, 158 mmol) in water (50mL) was then added at 0-5° C. and the mixture was stirred for anadditional 1 h at this temperature. The mixture was extracted with ethylacetate and the combined extracts were washed with brine and dried overNa₂SO₄. The filtrate was concentrated to afford the title compound as atan solid (2.19 g, 96% yield): ¹H NMR (400 MHz, CDCl₃): 7.53 (1 H, dd,J=8.8, 5.6 Hz), 6.94 (1 H, dd, J=8.8, 2.8 Hz), 6.79 (1 H, ddd, J=8.8,7.6, 2.8 Hz).

1-(2-Bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole. Amixture of 2-azido-1-bromo-4-fluorobenzene (1.047 g, 4.85 mmol) andtrimethylsilylacetylene (2.01 mL, 14.54 mmol) in toluene (5 mL) washeated in a pressure vessel at 110° C. for 21.5 h. The reaction mixturewas concentrated in vacuo and the residue was purified with a Biotagesystem on silica gel with hexanes:ethyl acetate (9:1) gradient as theeluent to afford the title compound as a colorless oil (1.451 g, 95%yield): ¹H NMR (400 MHz, CDCl₃) o ppm: 7.97 (1H, s), 7.74 (1H, dd,J=9.0, 5.4 Hz), 7.37 (1H, dd, J=8.5, 2.9 Hz), 7.16 (1 H, ddd, J=8.8,7.6, 3.0 Hz), 0.40 (9 H, s), LCMS (⁺ESI, M+H⁺) m/z 314/316.

1-(2-Bromo-5-fluorophenyl)-5-methyl-4-(trimethylsilyl)-1H-1,2,3-triazole.The title compound can be prepared according to the procedure providedfor 1-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.73-7.69 (1H, m), 7.20-7.16 (2H, m), 2.22(3H, s), 0.39 (9H, s); LCMS (⁺ESI, M+H⁺) m/z 328/330.

1-(2-Bromo-5-fluorophenyl)-4-tert-butyl-1H-1,2,3-triazole. The titlecompound can be prepared according to the procedure provided for1-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole ¹H NMR(400 MHz, CDCl₃) δ ppm: 7.68-7.75 (2 H, m), 7.38 (1 H, dd, J=8.5, 2.9Hz), 7.14 (1 H, ddd, J=8.8, 7.6, 3.0 Hz), 1.43 (9 H, s), LCMS (⁺ESI,M+H⁺) m/z 298/300.

1-(2-Bromo-5-fluorophenyl)-4-((tert-butyldimethylsilyloxy)methyl)-1H-1,2,3-triazole.The title compound can be prepared according to the procedure providedfor 1-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.95 (1 H, s), 7.75 (1 H, dd, J=9.0, 5.4Hz), 7.38 (1 H, dd, J=8.3, 3.0 Hz), 7.17 (1 H, ddd, J=9.0, 7.5, 2.8 Hz),4.96 (2 H, s), 0.93 (9 H, s), 0.13 (6 H, s), LCMS (⁺ESI, M+H⁺) m/z386/388.

1-(2-Bromo-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)-1H-1,2,3-triazole.The title compound can be prepared according to the procedure providedfor 1-(2-bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 1HNMR (400 MHz, CDCl₃) δ ppm: 7.70-7.78 (2 H, m), 7.19-7.30 (2 H, m), 4.67(2 H, s), 0.82 (9H, s), −0.03 (6 H, s), LCMS (⁺ESI, M+H⁺) m/z 386/388.

1-(2-Bromo-5-fluorophenyl)-1H-1,2,3-triazole.1-(2-Bromo-5-fluorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (0.80 g,2.55 mmol) was dissolved in tetrahydrofuran (10 mL) andtetrabutylammonium fluoride (2.8 mL, 2.80 mmol, 1.0 M intetrahydrofuran) was added dropwise and the reaction mixture was stirredat 25° C. for 4 h. The resulting mixture was concentrated in vacuo andthe residue was purified with a Biotage system on silica gel withhexanes:ethyl acetate (8:2 to 7:3) gradient as the eluent to afford thetitle compound as a white solid (0.36 g, 58% yield): ¹H NMR (400 MHz,CDCl₃) δ ppm: 8.06 (1 H, d, J=1.0 Hz), 7.90 (1 H, d, J=1.3 Hz), 7.76 (1H, dd, J=8.8, 5.3 Hz), 7.39 (1 H, dd, J=8.3, 2.8 Hz), 7.19 (1 H, ddd,J=8.9, 7.5, 3.0 Hz), LCMS (+ESI, M+H⁺) m/z 242/244.

1-(2-Bromo-5-fluorophenyl)-5-methyl-1H-1,2,3-triazole. The titlecompound can be prepared according to the procedure provided for1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole ¹H NMR (400 MHz, CDCl₃) δppm: 7.76 (1 H, dd, J=9.1, 5.3 Hz), 7.62 (1 H, s), 7.19-7.26 (2 H, m),2.25 (3 H, s), LCMS (⁺ESI, M+H⁺) m/z 256/258.

(1-(2-Bromo-5-fluorophenyl)-1H-1,2,3-triazol-4-yl)methanol. The titlecompound can be prepared according to the procedure provided for1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole ¹H NMR (400 MHz, CDCl₃) δppm: 8.02 (1 H, s), 7.75 (1 H, dd, J=8.8, 5.3 Hz), 7.38 (1 H, dd, J=8.2,2.9 Hz), 7.19 (1 H, ddd, J=8.9, 7.5, 3.0 Hz), 4.94 (2 H, s), LCMS (⁺ESI,M+H⁺) m/z 270/272.

4-Fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile. A mixture of1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole (0.603 g, 2.49 mmol), CuCN(0.245 g, 2.74 mmol), and 15 mL of NMP was subjected to microwaveirradiation at 150° C. for 0.5 h. The brown mixture was filtered overcelite and washed with dimethylfomamide. This solution was treated with10% aqueous NH₄OH (28-30% solution) and extracted with ethyl acetate.The combined organic layers were successively washed with 10% aqueousNH₄OH (28-30% solution), sat. NH₄Cl aq., water, brine and dried overNa₂SO₄. The resulting mixture was concentrated in vacuo and the residuewas purified with a Biotage system on silica gel with hexanes:ethylacetate (7:3 to 6:4) gradient as the eluent to afford the title compoundas a light yellow solid (0.285 g, 61% yield): ¹H NMR (400 MHz, CDCl₃) δppm: 8.40 (1 H, d, J=1.0 Hz), 7.96 (1 H, s), 7.91 (1 H, dd, J=8.6, 5.6Hz), 7.77 (1 H, dd, J=8.7, 2.4 Hz), 7.31-7.39 (1 H, m).

4-Fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile. The titlecompound can be prepared according to the procedure provided for4-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile ¹H NMR (400 MHz, CDCl₃) δppm: 7.93 (1 H, dd, J=8.7, 5.4 Hz), 7.67 (1 H, s), 7.44 (1 H, ddd,J=8.6, 7.6, 2.5 Hz), 7.35 (1 H, dd, J=8.1, 2.5 Hz), 2.39 (3 H, s), LCMS(⁺ESI, M+H⁺) m/z 203.

2-(4-tert-Butyl-1H-1,2,3-triazol-1-yl)-4-fluorobenzonitrile. The titlecompound can be prepared according to the procedure provided for4-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile ¹H NMR (400 MHz, CDCl₃) δppm: 8.07 (1 H, s), 7.87 (1 H, dd, J=8.8, 5.6 Hz), 7.74 (1 H, dd, J=8.8,2.5 Hz), 7.25-7.33 (1 H, m), 1.45 (9 H, s), LCMS (⁺ESI, M+H⁺) m/z 245.

4-Fluoro-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)benzonitrile. Thetitle compound can be prepared according to the procedure provided for4-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile ¹H NMR (400 MHz, CDCl₃) δppm: 8.34 (1 H, s), 7.91 (1 H, dd, J=8.7, 5.4 Hz), 7.74 (1 H, dd, J=8.6,2.5 Hz), 7.35 (1 H, ddd, J=8.8, 7.3, 2.5 Hz), 4.96 (2 H, s), LCMS (⁺ESI,M+H⁺) m/z 219.

(4-Fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl)methanamine hydrochloride. ¹HNMR (400 MHz, DMSO-D6) δ ppm: 8.73 (1 H, d, J=1.0 Hz), 8.53 (3 H, brs),8.07 (1 H, d, J=1.0 Hz), 7.91 (1 H, dd, J=8.7, 5.9 Hz), 7.66 (1 H, dd,J=9.2, 2.7 Hz), 7.60 (1 H, td, J=8.5, 2.7 Hz), 3.92(2 H, q, J=5.6 Hz),LCMS (⁺ESI, M+H⁺) m/z 193.

(4-Fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanaminehydrochloride;. ¹H NMR (400 MHz, DMSO-D6) δ ppm: 8.61 (2 H, s), 7.98 (1H, dd, J=9.5, 6.2 Hz), 7.80 (1 H, s), 7.61-7.67 (2 H, m), 3.66 (2 H, q,J=5.7 Hz), 2.26 (3H, s), LCMS (⁺ESI, M+H⁺) m/z 206.

(2-(4-tert-Butyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl)methanaminehydrochloride. ¹H NMR (400 MHz, DMSO-D6) δ ppm: 8.55 (2 H, brs), 8.52 (1H, s), 7.89 (1 H, dd, J=8.8, 6.1 Hz), 7.65 (1 H, dd, J=9.3, 2.5 Hz),7.55 (1 H, td, J=8.5, 2.5 Hz), 3.95 (2 H, q, J=5.6 Hz), 1.36 (9 H, s),LCMS (⁺ESI, M+H⁺) m/z 249.

(1-(2-(aminomethyl)-5-fluorophenyl)-1H-1,2,3-triazol-4-yl)methanolhydrochloride. ¹H NMR (400 MHz, DMSO-D6) δ ppm: 8.56 (1 H, s), 8.50 (2H, s), 7.89 (1 H, dd, J=8.7, 5.9 Hz), 7.63 (1 H, dd, J=9.2, 2.7 Hz),7.58 (1 H, td, J=8.5, 2.8 Hz), 4.65 (2 H, s), 3.94 (2 H, q, J=5.4 Hz),LCMS (⁺ESI, M+H⁺) m/z 223.

(2-(Chloromethyl)-1,3-dioxolan-2-yl)methyl acetate. A solution of1-acetoxy-3-chloroacetone (20.0 g, 133 mmol, TCI America) and1,2-bis(trimethylsilyloxy)ethane (30.2 g, 146 mmol, Aldrich) inanhydrous CH₂Cl₂ and under N₂ atmosphere was cooled (−78° C., dryice/acetone) and trimethylsilyl trifluoromethanesulfonate (1.2 mL, 6.6mmol, Aldrich) was added. The reaction was warmed to room temperatureand stirred for 5 days, with monitoring by ¹H-NMR. The crude reactionsolution was separated by silica gel column, and eluted with CH₂Cl₂,then 5% Et₂O in CH₂Cl₂. Product fractions were pooled and concentratedin-vacuo giving the title compound (19.05 g) as a yellow oil,contaminated with 1-acetoxy-3-chloroacetone (2.93 g) and CH₂Cl₂ (1.0 g):¹H NMR (500 MHz, CDCl₃) δ ppm 4.17 (2H, s), 4.03-4.11 (4H, m), 3.60 (2H,s), 2.09 (3H, s).

3-Chloro-2-cyano-2-(2-hydroxyethoxy)propyl acetate. A mixture of(2-(chloromethyl)-1,3-dioxolan-2-yl)methyl acetate (67.8 mmol),trimethylsilyl cyanide (20.29 g, 204 mmol, TCI America) and zinc iodide(3.65 g, 11.4 mmol) was heated (40° C., oil bath) for 6 hrs, then atambient temperature for 16 hrs. The mixture was diluted with CH₂Cl₂ (100mL) and stirred with silica gel (50 g) for several hours. The mixturewas loaded onto a flash silica gel column (350 g silica) and eluted withCH₂Cl₂ then increasing amounts of Et₂O to a final eluent of 30% Et₂O inCH₂Cl₂. Product fractions were pooled and concentrated in-vacuo to givethe title compound as an amber oil: ¹H NMR (500 MHz, CDCl₃) δ ppm 4.44(1H, d, J=-11.90 Hz), 4.35 (1H, d, J=11.90 Hz), 3.83-3.88 (2H, m),3.79-3.84 (4H, m), 2.13-2.16 (3H, m); LC/MS m/z 222.16 (M+H).

2-(Chloromethyl)-3-(hydroxyamino)-2-(2-hydroxyethoxy)-3-iminopropylacetate. A solution of 3-chloro-2-cyano-2-(2-hydroxyethoxy)propylacetate (9.40 g, 42.4 mmol) in ethanol (150 mL) was treated with 50%aqueous hydroxylamine solution (2.94 g, 44.5 mmol, Aldrich) and thereaction was heated (65° C.) for 1.5 hrs. The solution was cooled toroom temperature and the product was used as-is in the subsequentreaction: LC/MS m/z 255.20 (M+H).

2-{[3-Acetoxy-2-chloromethyl-2-(2-hydroxy-ethoxy)-propionimidoyl]-aminooxy}-but-2-enedioicacid diethyl ester. The ethanol solution of2-(chloromethyl)-3-(hydroxyamino)-2-(2-hydroxyethoxy)-3-iminopropylacetate, obtained above, was treated with diethyl acetylenedicarboxylate(46.6 mmol, Alfa Aesar) and stirred 16 hrs. Solvent was removed in-vacuoand the resultant amber oil was dissolved in ethyl acetate (100 mL) andwashed with water (2×100 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated in-vacuo. The crude product was purified byflash column chromatography, eluting with 30%-50% ethyl acetate inhexanes. Product fractions were pooled and concentrated in-vacuo to givethe title compound (11.1 g) as a viscous amber oil: LC/MS m/z 425.19(M+H).

Ethyl2-(3-acetoxy-1-chloro-2-(2-hydroxyethoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate.A solution of2-{[3-acetoxy-2-chloromethyl-2-(2-hydroxy-ethoxy)-propionimidoyl]-aminooxy}-but-2-enedioicacid diethyl ester (11.1 g, 26.13 mmol) in 1,2,4-trimethyl benzene (260mL, Aldrich) was heated at reflux (160° C., oil bath) for 90 minutes.The reaction was cooled and the solvent was removed in-vacuo. The crudeproduct was dissolved in ethyl acetate (100 mL) and extracted intosaturated NaHCO₃ aqueous solution (4×50 mL). The combined extracts werebrought to pH˜1 using 6.0 N HCl, and re-extracted into ethyl acetate(3×75 mL). The combined extracts were dried (Na₂SO₄), filtered, andconcentrated in-vacuo to give a pale yellow solid This was trituratedwith Et₂O, and solids were collected by filtration, followed by dryingin-vacuo, to give the title compound as an off-white solid: ¹H NMR (500MHz, CDCl₃) δ ppm 12.13 (1H, br), 10.86 (1H, br), 4.76 (1H, d, J=11.90Hz), 4.44 (2H, q, J=7.02 Hz), 4.32 (1H, d J=11.90 Hz), 4.08 (1H, d,J=12.5), 4.00 (1H, d, J=12.5), 3.83-3.95 (2H, m), 3.66-3.78 (2H, m),2.02 (3H, s), 1.42 (3H, t, J=7.17 Hz); ¹³NMR (126 MHz, CDCl₃) δ ppm170.23, 168.97, 159.39, 150.15, 147.87, 126.88, 79.86, 65.94, 63.91,62.86, 61.37, 44.33, 20.78, 14.20; HRMS (ESI) calcd for C₁₄H₂₀N₂O₈Cl(M+H) 379.0908; found 379.0896.

Ethyl9-(acetoxymethyl)-9-(chloromethyl)-3-(methylsulfonyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of ethyl2-(3-acetoxy-1-chloro-2-(2-hydroxyethoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate(2.322 g, 6.13 mmol) in tetrahydrofuran (100 mL) was treated withmethane sulfonylchloride (2.11 g, 18.4 mmol) and Et₃N (2.25 g, 22 mmol)and then heated (60° C., oil bath) for 3 hrs. Solvent was removedin-vacuo and the crude product was dissolved in ethyl acetate (100 mL),then washed with water (2×50 mL). The organic solution was dried(Na₂SO₄), filtered and concentrated in-vacuo to give the title compoundas a viscous amber oil which was used immediately in the followingreaction.

Ethyl9-(acetoxymethyl)-9-(chloromethyl)-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of ethyl9-(acetoxymethyl)-9-(chloromethyl)-3-(methylsulfonyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate,obtained above, in absolute ethanol (120 mL) was treated with solidsodium ethoxide (0.440 g, 6.13 mmol, 95%, Aldrich) and stirred for 30min. The reaction was monitored by HPLC, and additional sodium ethoxidein ethanol (0.5 mL, 1.34 mmol, 21 wt %, Aldrich) was added. The reactionwas stirred 20 minutes and then concentrated in-vacuo. The crudematerial was dissolved in ethyl acetate (20 mL) and washed with 0.05 NHCl aqueous solution (40 mL). The organic solution was dried (Na₂SO₄),filtered, and concentrated in-vacuo to give the title compound (2.05 g)as an amber oil: LC/MS m/z 361.19 (M+H)

Ethyl9-(acetoxymethyl)-3-(benzyloxy)-9-(chloromethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate.A solution of ethyl9-(acetoxymethyl)-9-(chloromethyl)-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(2.05 g, 5.68 mmol) in dimethylfomamide (60 mL) was treated with benzylbromide (1.46 g, 8.5 mmol, Aldrich) and K₂CO₃ (1.26 g, 9.1 mmol) andstirred for 16 hrs. Solvent was removed in-vacuo and the crude materialwas dissolved in ethyl acetate (30 mL) and washed with water (30 mL) andbrine (30 mL). The organic solution was dried (Na₂SO₄), filtered, andconcentrated to give an amber oil. This was purified by flash columnchromatography, eluting with 5% Et₂O in CH₂Cl₂. Product fractions werepooled and concentrated in-vacuo to give the title compound as acolorless oil: ¹H NMR (500 MHz, CDCl₃) δ ppm 7.45 (2H, d, J=7.32 Hz),7.29-7.39 (3H, m), 4.68 (1H, d, J=1 1.90 Hz), 4.37 (1H, d, J=1 1.90 Hz),4.31 (2H, q, J=7.22 Hz), 4.16-4.24 (2H, m), 4.09-4.16 (1H, m), 4.06 (1H,d, J=11.29 Hz), 3.95-4.03 (1H, m), 3.89 (1H, d, J=1 1.29 Hz), 2.06 (3H,s), 1.56 (2H, s), 1.29 (3H, t, J=7.17 Hz); ¹³C NMR (126 MHz, CDCl₃) δppm 170.16, 164.04, 158.67, 150.65, 141.94, 141.67, 136.51, 128.59128.52, 128.45, 79.57, 74.51, 65.90, 62.11, 60.59, 49.08, 42.16, 20.83,14.16; HRMS (ESI) calcd for C₂₁H₂₄N₂O₇Cl (M+H) 451.1272; found 451.1274.

N-(4-Fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-9-(chloromethyl)-3-hydroxy-9-(hydroxymethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide.A solution of ethyl9-(acetoxymethyl)-3-(benzyloxy)-9-(chloromethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate(1.0 g) in trifluoroacetic acid (5 mL) CH₂Cl₂ (5 mL) was stirred for 2hrs. An aliquot was transferred to a separate reaction flask andconcentrated to give des-OBn intermediate (0.363 g, 1.01 mmol). This wasimmediately dissolved in dimethylfomamide (2 mL) and ethanol (2 mL) andtreated with (4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzylaminehydrochloride (0.320 g, 1.31 mmol) and triethyl amine (0.75 mL, 5.2mmol), and heated (90° C.) for 5 hrs. To the reaction was added Cs₂CO₃(0.340 g, 1.1 mmol) and water (1 mL) and the reaction stirred for 2.5hrs. The reaction was concentrated in-vacuo and the resultant crudematerial was suspended in water (10 mL) and extracted into CH₂Cl₂ (2×10mL). The combined extracts were dried (Na₂SO₄), filtered, andconcentrated to give a solid which was then triturated with a smallvolume of 95% ethanol. The resultant precipitate was collected byfiltration and dried in-vacuo to give the title compound as a whitecrystalline solid: ¹H NMR (500 MHz, CDCl₃) δ ppm 12.18-12.31 (1H, m),8.49 (1H, t, J=6.26 Hz), 8.32 (1H, s), 7.67 (1H, dd, J=8.39, 5.95 Hz),7.19 (1H, dt, J=8.16, 2.29 Hz), 7.08 (1H, dd, J=8.39, 2.29Hz), 5.29 (2H,s), 4.54 (1H, dd, J=14.19, 6.87 Hz), 4.19-4.27 (1H, m), 4.12-4.18 (1H,m), 4.10 (2H, t, J=4.58 Hz), 4.00 (2H, t, J=12.21 Hz), 3.90-3.96 (2H,m), 2.55 (3H, s); ¹³C NMR (126 MHz, CDCl₃) δ ppm 167.69, 163.26, 162.49,157.34, 147.41, 146.32, 144.26, 134.31, 134.24, 128.45, 128.42, 125.59,116.93, 116.76, 112.41, 112.21, 80.41, 66.93, 60.79, 53.52, 48.62,42.47, 39.41, 14.12; HRMS ESI) calcd for C₂₀H₂₁N₆O₅FCl (M+H) 479.1246,found 479.1224; Elem. Anal. calcd for C₂₀H₂₀N₆O₅FCl: C 49.79, H 4.26, N17.42, found: C 50.11, H 4.10, N 17.28.

2-(3-Methyl-1H-1,2, 4-triazol-1-yl)benzonitrile. White crystals; mp109-110° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.54(3H, s, CH₃), 7.5-7.58 (1H, m, aromatic), 7.75-7.8 (2H, m, aromatics),7.82-7.86 (1H, m, aromatic), 8.68 (1H, s, CH). Anal. Calcd for C₁₀H₈N₄:C 65.20, H 4.37, N 30.41; Found: C 64.99, H 4.09, N 30.50.

(2-(3-Methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride.White solid. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.41 (3H, s, CH₃), 4.01(2H, m, CH₂), 7.6 (3H, m, aromatics), 7.78 (1H, m, aromatic), 8.5(broad, NH), 8.98 (1H, s, CH). MS (ESI⁺) m/e 189 [M+H⁺].

2-(5-Methyl-1H-1,2,4-triazol-1-yl)benzonitrile. White crystals; mp119-120° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.52(3H, s, CH₃), 7.55 (1H, m, aromatic), 7.67 (1H, m, aromatic), 7.82 (1H,m, aromatic), 7.89 (1H, m, aromatic), 8.05 (1H, s, CH). Anal. Calcd forC₁₀H₈N₄: C 65.20, H 4.37, N 30.41; Found: C 64.97, H 4.07, N 30.42.

(2-(5-Methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride.White solid. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.38 (3H, s, CH₃), 3.80(2H, m, CH₂), 7.56-7.7 (3H, m, aromatics), 7.8-7.82 (1H, m, aromatic),8.17 (1H, s, CH), 8.44 (broad, NH). MS (ESI⁺) m/e 189 [M+H⁺].

Ethyl5-hydroxy-2-(4-(3-hydroxypropoxy)-tetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate.Clear yellow oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.43 (3H, t, J=7.1 Hz,CH₃), 1.8-2.3 (6H, m, 3×CH₂), 3.44 (2H, t, J=5.5 Hz, CH₂), 3.6-4.0 (6H,m, 3×CH₂), 4.44 (2H, q, J=7.1 Hz, OCH₂), 10.8 (1H, broad, OH). HRMS(ESI⁺) calculated for C₁₅H₂₃N₂O₇ [M+H⁺]: 343.1505; found: 343.1499.

White crystals; mp 140-142° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.46 (3H, t, J=7.1 Hz, CH₃), 1.86 (2H, m, CH₂), 2.02 (2H, m,CH₂), 2.43 (2H, m, CH₂), 3.75 (2H, m, CH₂), 3.83-3.91 (4H, m, 2×CH₂),4.46 (2H, q, J=7.1 Hz, OCH₂), 4.6 (2H, broad m, CH₂), 10.62 (1H, broad,OH). Anal. Calcd for C₁₅H₂₀N₂O₆: C 55.55, H 6.21, N 8.63; Found: C55.56, H 6.22, N 8.55.

Clear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.33 (3H, t, J=7.1 Hz, CH₃),1.86 (2H, m, CH₂), 2.03 (2H, m, CH₂), 2.42 (2H, m, CH₂), 3.77 (2H, m,CH₂), 3.8-3.9 (4H, m, 2×CH₂), 4.36 (2H, q, J=7.1 Hz, OCH₂), 4.55 (2H,broad m, CH₂), 5.28 (2H, s, OCH₂), 7.3-77.4 (3H, m, aromatics), 7.5 (2H,m, aromatics). MS (ESI⁺) m/e 415 [M+H⁺].

White crystals; mp 185-186° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.89 (2H, m, CH₂), 2.06 (2H, m, CH₂), 2.34 (2H, m, CH₂), 3.77(2H, m, CH₂), 3.8-3.92 (4H, m, 2×CH₂), 4.58 (2H, broad m, CH₂), 5.50(2H, s, OCH₂), 7.3-7.4 (3H, m, aromatics), 7.56 (2H, m, aromatics).Anal. Calcd for C₂₀H₂₂N₂O₆: C 62.16, H 5.73, N 7.25; Found: C 62.29, H5.78, N 7.17.

EXAMPLE 1

A mixture of ester 3 (0.146 g, .499 mmol), 4-fluorobenzylamine (0.156 g,1.25 mmol, and triethylamine (0.14 mL, 1 mmol) in 1:1 DMF/EtOH (2 mL)was heated at 110° C. for 1.5 h. Then, the reaction mixture was cooledand purified preparative HPLC using MeOH/water containing 0.1 F TFA(gradient elution). The fractions containing the product were combinedand evaporated to afforded the product as a white solid (0.0955 g,51.5%). ¹H NMR (500 MHz, CDCl₃) δ: 11.70 (1H, s), 7.86 (1H, br t),7.32-7.29 (2H, m), 7.05 (2H, t, J=8.6 Hz), 4.59 (2H, d, J=6.4 Hz), 4.01(2H, t, J=6.4 Hz), 2.16-2.11 (2H, m), 1.99-1.94 (2H, m), 1.82-1.65 (8H,m). HRMS (M+H) calcd for C₂₀H₂₃FN₃O₃: 372.1724; found: 371.1714. Analcald for C₂₀H₂₂FN₃O₃: C, 64.67; H, 5.97; N, 11.31. Found: C, 64.58; H,6.24; N, 11.11.

Other examples made by similar methods using amine (2-10 equiv), Et₃N(2-10 equiv.) and appropriate ester in DMF, DMF/EtOH, or other solventsystem at 60° C.-140° C. are listed in Table 3.

TABLE 3 Ex. Structure Data 2

Yield: 43%. ¹H NMR (500 MHz, CDCl₃) δ:11.72 (1H, s), 7.84 (1H, br t),7.15-7.09(2H, m), 6.99 (1H, t, J=8.9 Hz), 4.55 (2H,d, J=6.1 Hz), 4.01(2H, t, J=6.4 Hz), 2.28(3H, s), 2.17-2.12 (2H, m), 1.99-1.94 (2H,m),1.83-1.65 (8H, m). HRMS (M + H) calcdfor C₂₁H₂₅FN₃O₃: 386.188;found:386.1875. Anal cald for C₂₁H₂₄FN₃O₃.0.03H₂O.0.05 CH₂Cl₂: C, 64.79;H, 6.24; N,10.77; found: C, 64.71; H, 6.31; N, 10.71. 3

Yield: 65%. ¹H NMR (500 MHz, CDCl₃) δ:11.82 (1H, s), 8.80 (1H, t, J=6.1Hz), 8.43(1H, s), 8.15 (1H, s), 7.73 (1H, dd, J=7.3,1.5 Hz), 7.52-7.44(2H, m), 7.36 (1H, dd, J=7.6, 1.2 Hz), 4.48 (2H, d, J=6.7 Hz),3.99 (2H,t, J=6.4 Hz), 2.28-2.23 (2H, m),1.99-1.91 (4H, m), 1.79-1.66 (6H,m).HRMS (M + H) calcd for C₂₂H₂₅N₆O3:421.1988; found: 421.2001. Analcald forC₂₂H₂₄N₆O₃: C, 62.84; H, 5.75; N, 19.98;found: C, 62.55; H,5.68; N, 20.03. 4

Yield: 70%. ¹H NMR (500 MHz, CDCl₃) δ:11.76 (0.6H, s), 11.69 (0.4H, s),8.77 (0.6H,t, J=6.4 HZ), 8.68 (0.4H, t, J=6.4 Hz),8.44 (0.6H, s), 8.39(0.4H, s), 8.16 (0.6H,s), 8.15 (0.4H, s), 7.73 (0.H, dd, J=8.6, 6.1Hz),7.43 (0.4H, dd, J=8.6, 2.8 Hz), 7.34(0.4H, dd, J=8.5, 4.9 Hz), 7.21(0.6H, td, J=8.2, 2.4 Hz), 7.15 (0.4H, td, J=8.5,3.0 Hz), 7.11 (0.6H,dd, J=8.6 2.4 Hz), 4.45(0.6H, d, J=6.7 Hz), 4.43 (0.4H, d, J=7.0Hz),4.04-3.98 (2H, m), 2.27-2.22 (2H, m),1.98-1.91 (4H, m), 1.81-1.66(6H, m).HRMS (M + H) calcd for C₂₂H₂₄FN₆O₃:439.1894; found: 439.1887.Anal cald forC₂₂H₂₃FN₆O₃: C, 60.26; H, 5.28; N, 19.16;found: C, 60.10;H, 5.42; N, 19.25. 5

Yield: 71%. ¹H NMR (500 MHz, CDCl₃) δ:11.77 (0.6H, s), 11.70 (0.4H, s),8.80 (0.6H,t, J=6.7 Hz), 8.70 (0.4H, t, J=6.4 Hz),8.44 (0.6H, s), 8.39(0.4H, s), 8.16 (0.6H,s), 8.15 (0.4H, s), 7.73 (0.6H, dd, J=8.5,6.1 Hz),7.43 (0.4H, dd, J=8.6, 2.8 Hz),7.34 (0.4H, dd, J=8.9, 4.9 Hz), 7.21(0.6H,td, J=8.2, 2.7 Hz), 7.15 (0.4H, td, J=8.6,2.8 Hz), 7.11 (0.6H, dd,J=8.4, 2.6 Hz),4.45 (0.6H, d, J=6.7 Hz), 4.43 (0.4H, d, J=6.7 Hz),4.01-3.98 (2H, m), 2.27-2.22(2H, m), 1.98-1.92 (4H, m), 1.80-1.66(6H,m). HRMS (M + H) calcd for C₂₂H₂₄FN₆O₃:439.1894; found: 439.1875.Anal cald forC₂₂H₂₃FN₆O₃: C, 60.26; H, 5.28; N, 19.16;found: C, 60.14;H, 5.38; N, 19.25. 6

Yield: 73%. ¹H NMR (500 MHz, CDCl₃) δ:11.87 (1H, s), 8.91 (1H, t, J=6.7Hz), 7.91(2H, s), 7.69 (1H, dd, J=8.5, 5.8 Hz), 7.63(1H, dd, J=9.3, 2.6Hz), 7.13 (1H, td, J=8.2, 2.6 Hz), 4.64 (2H, d, J=7.0 Hz), 3.99(2H, t,J=6.4 Hz), 2.23-2.17 (2H, m), 1.97-1.85(4H, m), 1.78-1.63 (6H, m).HRMS(M + H) calcd for C₂₂H₂₄FN₆O₃: 439.1894;found: 439.1912. Anal caldforC₂₂H₂₃FN₆O₃: C, 60.26; H, 5.28; N, 19.16;found: C, 59.97; H, 4.99; N,19.03. 7

Yield: 63%. ¹H NMR (500 MHz, CDCl₃) δ:13.02 (1H, br s), 8.82 (1H, s),7.98 (1H, t, J=5.2 Hz), 7.60-7.57 (2H, m), 7.47 (1H, s),7.33 (1H, td,J=7.6, 1.8 Hz), 7.13 (1H, d, J=7.3 Hz), 4.39 (2H, d, J=5.8 Hz), 3.99(2H,t, J=6.4 Hz), 2.16-2.10 (2H, m), 1.99-1.94 (2H, m), 1.86-1.67 (8H, m).HRMS(M + H) calcd for C₂₃H₂₅FN₅O₃: 438.1941;found: 438.1954. Anal caldforC₂₃H₂₄FN₅O₃.0.3 EtOAc: C, 50.92; H, 4.37;N, 10.84; found: C, 50.59;H, 4.14; N,10.95. 8

Yield: 77%. ¹H NMR (500 MHz, CDCl₃) δ:11.90 (1H, s), 8.22-8.20 (1H, m),7.47-7.43(2H, m), 7.36-7.32 (2H, m), 4.98 (1H, dd, J=14.3, 8.5 Hz), 4.46(1H, dd, J=14.3, 4.0 Hz),3.99 (2H, td, J=6.2, 1.8 Hz), 3.90-3.85 (1H,m), 3.44-3.39 (1H, m), 3.25-3.22(2H, m), 2.44-2.30 (2H, m), 2.23-2.15(2H,m), 1.97-1.89 (4H, m), 1.85-1.80 (2H, m),1.73-1.58 (6H, m).HRMS (M + H) calcd forC₂₄H₃₁N₄O₅S: 487.2015; found: 487.2030.Anal caldfor C₂₄H₃₀N₄O₅S: C, 59.24; H,6.21; N, 11.51; found: C, 58.94; H, 6.47;N,11.43. 9

Yield: 70%. ¹H NMR (500 MHz, CDCl₃) δ:11.85 (1H, s), 8.22-8.19 (1H, m),7.46 (1H,dd, J=8.6, 6.4 Hz), 7.16 (1H, dd, J=9.2,2.5 Hz), 7.06 (1H, td,J=8.2, 2.8 Hz), 4.95(1H, dd, J=14.3, 8.9 Hz), 4.39 (1H, dd, J=14.3, 4.0Hz), 3.99 (2H, td, J=6.4, 1.8 Hz),3.86-3.81 (1H, m), 3.43-3.39 (1H, m),3.25-3.23 (2H, m), 2.44-2.30 (2H, m), 2.22-2.14(2H, m), 1.98-1.90 (4H,m), 1.85-1.80 (2H,m), 1.74-1.58 (6H, m). HRMS (M + H) calcdforC₂₄H₃₀FN₄O₅S: 505.1921; found:505.1942. Anal cald for C₂₄H₂₉FN₄O₅S:C,57.13; H, 5.79; N, 11.10; found: C, 57.01;H, 5.98; N, 11.02. 10

Yield: 66%. ¹H NMR (500 MHz, CDCl₃) δ:11.65 (1H, br s), 8.60 (1H, t,J=6.7 Hz),7.69 (1H, dd, J=8.4, 5.4 Hz), 7.49 (1H, dd,J=8.4, 2.6 Hz),7.28-7.24 (1H, m), 4.81(2H, d, J=6.7 Hz), 3.98 (2H, t, J=6.4 Hz),2.89(6H, s), 2.22-2.16 (2H, m), 1.96-1.91(4H, m), 1.76-1.61 (6H, m). HRMS(M + H)calcd for C₂₂H₂₈FN₄O₅S: 479.1764; found:479.1788. Anal cald forC₂₂H₂₇FN₄O₅S.0.8H₂O: C, 53.60; H, 5.85; N, 11.37; found:C, 53.48; H,5.50; N, 10.98. 11

Yield: 53%. ¹H NMR (500 MHz, CDCl₃) δ:11.54 (1H, s), 8.56 (1H, t, J=6.4Hz), 7.74(1H, dd, J=8.1, 2.6 Hz), 7.71 (1H, dd, J=8.6, 5.2 Hz), 7.33(1H, td, J=8.1, 2.8 Hz),4.83 (2H, d, J=7.0 Hz), 3.97 (2H, t, J=6.4Hz),3.16 (3H, s), 2.20-2.15 (2H, m), 1.96-1.91 (4H, m), 1.76-1.62 (6H,m). HRMS(M + H) calcd for C₂₁H₂₅FN₃O₅S: 450.1499;found: 450.1479. Analcald forC₂₁H₂₄FN₃O₅S: C, 56.11; H, 5.38; N, 9.34;found: C, 55.89; H,5.39; N, 9.19. 12

Yield: 66%. ¹H NMR (500 MHz, CDCl₃) δ:11.73 (1H, s), 8.71 (1H, t, J=6.4Hz), 8.45(1H, d, J=3.4 Hz); 8.18 (1H, s), 7.51 (1H,d, J=7.6 Hz),7.48-7.43 (1H, m), 7.27-7.23(1H, m), 4.43 (2H, d, J=6.7 Hz), 3.99 (2H,t,J=6.4 Hz), 2.28-2.22 (2H, m), 2.00-1.92(4H, m), 1.81-1.74 (4H, m),1.72-1.67 (2H,m). HRMS (M + H) calcd for C₂₂H₂₄FN₆O₃:439.1894; found:439.1883. Anal cald forC₂₂H₂₃FN₆O₃: C, 60.26; H, 5.28; N, 19.16;found:C, 60.06; H, 5.22; N, 19.09. 13

Yield: 59%. ¹H NMR (500 MHz, CDCl₃) δ:11.90 (1H, s), 7.93 (1H, br t),7.34-7.32(2H, m), 7.05 (2H, t, J=8.5 Hz), 4.60 (2H,d, J=6.4 Hz), 3.99(2H, t, J=6.4 Hz),3.90-3.90 (2H, m), 3.65 (2H, dt=11.9, 1.5 Hz),2.38(2H, dt, J=13.5, 3.7 Hz), 2.03-1.94 (4H, m), 1.52 (2H, d, J=13.7Hz).HRMS (M − H) calcd for C₂₀H₂₁FN₃O₄:386.1516; found: 386.1499. Analcald forC₂₀H₂₂FN₃O₄.0.04 H₂O.0.2 TFA: C, 64.79;H, 6.24; N, 10.77; found:C, 64.71; H, 6.31;N, 10.71. 14

Yield: 79%. ¹H NMR (500 MHz, CDCl₃) δ:12.01 (1H, s), 7.78 (1H, br t),7.39-7.30(5H, m), 4.63 (2H, d, J=6.4 Hz), 4.03-3.96(4H, m), 2.16-2.04(4H, m), 1.86-1.79 (4H,m). HRMS (M + H) calcd for C₁₉H₂₂N₃O₄:356.1610;found: 356.1616. Anal cald forC₁₉H₂₁N₃O₄: C, 64.21; H, 5.95; N,11.82;found: C, 63.98; H, 5.81; N, 11.71. 15

Yield: 85%. ¹H NMR (500 MHz, CDCl₃) δ:11.92 (1H, s), 7.75 (1H, brt),7.30 (2H, dd,J=8.5, 5.5 Hz), 7.04 (2H, t, J=8.5 Hz),4.58 (2H, d, J=6.4Hz), 4.02-3.95 (4H, m),2.15-2.04 (4H, m), 1.88-1.79 (4H, m).HRMS (M + H)calcd for C₁₉H₂₁FN₃O₄:374.1516; found: 374.1506. Anal caldforC₁₉H₂₀FN₃O₄.0.15 H₂O: C, 60.09; H, 5.37;N, 11.01; F, 5.72; found: C,59.87; H, 5.24;N, 10.90; F, 5.53. 16

Yield: 67%. ¹H NMR (500 MHz, CDCl₃) δ:11.95 (1H, s), 7.72 (1H, brt),7.14 (1H, d, J=7.0 Hz), 7.11-7.08 (1H, m), 6.98 (1H, t, J=9.0 Hz), 4.54(2H, d, J=6.4 Hz), 4.03-3.95 (4H, m), 2.27 (3H, s), 2.16-2.03 (4H,m),1.88-1.79 (4H, m). HRMS (M + H) calcdfor C₂₀H₂₃FN₃O₄: 388.1673;found:388.1661. 17

Yield: 51%. ¹H NMR (500 MHz, CDCl₃) δ:11.90 (1H, s), 8.76 (1H, t, J=6.4Hz), 8.44(1H, s), 8.13 (1H, s), 7.70 (1H, dd, J=8.5,6.1 Hz), 7.21 (1H,td, J=8.2, 2.4 Hz), 7.11(1H, dd, J=8.4, 2.6 Hz), 4.44 (2H, d, J=6.7 Hz),4.01-3.94 (4H, m), 2.27-2.21 (2H,m), 2.09-2.04 (2H, m), 1.93-1.88 (4H,m).HRMS (M + H) calcd for C₂₁H₂₂FN₆O₄:441.1687; found: 441.1691. Analcald forC₂₁H₂₁FN₆O₄: N, 19.08; F, 4.31; found: N,19.37; F, 4.56. 18

Yield: 77%. ¹H NMR (500 MHz, CDCl₃) δ:11.84 (1H, s), 8.08 (1H, t, J=5.2Hz), 7.30(1H, dd, J=8.4, 6.0 Hz), 6.95 (1H, dd, J=9.5, 2.7 Hz), 6.83(1H, td, J=8.2, 2.8 Hz),4.60 (2H, d, J=6.4 Hz), 4.01-3.94 (4H, m),2.51(3H, s), 2.20-2.14 (2H, m), 2.08-2.03(2H, m), 1.88-1.82 (4H, m). HRMS(M + H)calcd for C₂₀H₂₃FN₃O₃S: 420.1393; found:420.1383. Anal cald forC₂₀H₂₂FN₃O₃S: C,57.26; H, 5.28; N, 10.01; F, 4.52; found: C,57.27; H,5.31; N, 10.01; F, 4.49. 19

Yield: 83%. ¹H NMR (500 MHz, CDCl₃) δ:12.04 (1H, s) 7.74 (1H, brt), 7.22(2H, d, J=7.9 Hz), 7.18 (2H, d, J=7.9 Hz), 4.58(2H, d, J=6.1 Hz),4.03-3.95 (4H, m), 2.35(3H, s), 2.15-2.03 (4H, m), 1.87-1.79 (4H,m).HRMS (M + H) calcd for C₂₀H₂₄N₃O₄:370.1767; found: 370.1778. Anal caldforC₂₀H₂₃N₃O₄: C, 65.02; H, 6.27; N, 11.37;found: C, 64.93; H, 6.44; N,11.32. 20

Yield: 75%. ¹H NMR (500 MHz, CDCl₃) δ:11.90 (1H, s), 7.76 (1H, t, J=5.4Hz), 7.34(2H, d, J=7.9 Hz), 7.26 (2H, d, J=7.9 Hz),4.59 (2H, d, J=6.4Hz), 4.03-3.96 (4H, m),2.16-2.04 (4H, m), 1.89-1.79 (4H, m).HRMS (M + H)calcd for C₁₉H₂₁ClN₃O₄:3901221; found: 390-1216. Anal caldforC₁₉H₂₀ClN₃O₄: C, 58.54; H, 5.17; N, 10.77;found: C, 58.34; H, 5.24;N, 10.59. 21

Yield: 73%. ¹H NMR (500 MHz, CDCl₃) δ:11.81 (1H, s), 7.79 (1H, t, J=5.4Hz), 7.43(1H, d, J=8.2 Hz), 7.41 (1H, d, J=1.5 Hz),7.17 (1H, dd, J=8.2,1.5 Hz), 4.57 (2H, d,J=6.4 Hz), 4.03-3.96 (4H, m), 2.17-2.05(4H, m),1.90-1.81 (4H, m). HRMS (M + H)calcd for C₁₉H₂₀Cl₂N₃O₄: 424.0831;found:424.0811. 22

Yield: 85%. ¹H NMR (500 MHz, CDCl₃) δ:12.06 (1H, s), 7.74 (1H, br t),7.13 (1H, d, J=7.6 Hz), 7.09 (1H, s), 7.05 (1H, d, J=7.6 Hz),4.56 (2H,d, J=6.1 Hz), 4.03-3.95(4H, m), 2.26 (6H, s), 2.16-2.03 (4H,m),1.87-1.80 (4H, m). HRMS (M + H) calcd forC₂₁H₂₆N₃O₄: 384.1923; found:384.1937.Anal cald for C₂₁H₂₅N₃O₄: C, 65.78; H,6.57; N, 10.95; found: C,65.58; H, 6.58; N,10.89. 23

Yield: 84%. ¹H NMR (500 MHz, CDCl₃) δ:12.04 (1H, s), 7.71 (1H, br t),7.26 (2H, d, J=8.6 Hz), 6.90 (2H, d, J=8.6 Hz), 4.55(2H, d, J=6.4 Hz),4.03-3.95 (4H, m), 3.81(3H, s), 2.15-2.03 (4H, m), 1.87-1.79 (4H,m).HRMS (M + H) calcd for C₂₀H₂₄N₃O₅:386.1716; found: 386.1697. Anal caldforC₂₀H₂₃N₃O₅.0.11 CH₂Cl₂: C, 61.19; H,5.93; N, 10.64; found: C, 60.86;H, 5.98; N, 10.55. 24

Yield: 78%. ¹H NMR (500 MHz, CDCl₃) δ:11.89 (1H, s), 7.88 (1H, t, J=5.2Hz), 7.37(1H, td, J=7.6 1.2 Hz), 7.33-7.28 (1H, m),7.14 (1H, t, J=7.6Hz), 7.09 (1H, t, J=9.3 Hz),4.66 (2H, d, J=6.4 Hz), 4.03-3.95(4H, m),2.19-2.13 (2H, m), 2.09-2.04 (2H,m), 1.89-1.83 (4H, m). HRMS (M + H)calcdfor C₁₉H₂₁FN₃O₄: 374.1516; found:374.1532. Anal cald forC₁₉H₂₀FN₃O₄.0.05Et₂O.0.05 CH₂Cl₂: C, 60.63; H, 5.45; N,11.02; found: C,60.58; H, 5.33; N, 11.03. 25

Yield: 88%. ¹H NMR (500 MHz, CDCl₃) δ:12.10 (1H, s), 8.06 (1H, t, J=5.6Hz), 7.20(1H, d, J=8.2 Hz), 6.48 (1H, d, J=2.4 Hz),6.45 (1H, dd, J=8.2,2.4 Hz), 4.51 (2H, d,J=6.4 Hz), 4.01-3.95 (4H, m), 3.85 (3H, s),3.80(3H, s), 2.20-2.14 (2H, m), 2.09-2.04(2H, m), 1.91-1.83 (4H, m). HRMS(M + H)calcd for C₂₁H₂₆N₃O₆: 416.1822; found:416.1837. Anal cald forC₂₁H₂₅N₃O₆: C,60.71; H, 6.06; N, 10.11; found: C, 60.47;H, 6.10; N,9.97. 26

Yield: 86%. ¹H NMR (500 MHz, CDCl₃) δ:11.89 (1H, s), 7.80 (1H, br t),7.34 (1H, q, J=7.6 Hz), 7.10 (1H, d, J=7.6 Hz), 7.03-6.98 (2H, m), 4.62(2H, d, J=6.4 Hz), 4.04-3.96 (4H, m), 2.17-2.05 (4H, m), 1.88-1.81(4H,m). HRMS (M + H) calcd forC₁₉H₂₁FN₃O₄: 374.1516; found: 374.1504.Analcald for C₁₉H₂₀FN₃O₄.0.1 CH₂Cl₂: C,60.07; H, 5.33; N, 11.00; found: C,60.06;H, 5.39; N, 10.94. 27

Yield: 65%. ¹H NMR (500 MHz, CDCl₃) δ:11.93 (1H, s), 7.76 (1H, br t),7.17 (1H, t, J=7.9 Hz), 6.99 (1H, d, J=7.9 Hz), 6.97(1H, d, J=10.4 Hz),4.57 (2H, d, J=6.4 Hz),4.03-3.96 (4H, m), 2.26 (3H, s), 2.17-2.05 (4H,m), 1.88-1.80 (4H, m). HRMS(M + H) calcd for C₂₀H₂₃FN₃O₄:388.1673;found: 388.1665. Anal cald forC₂₀H₂₂FN₃O₄: C, 62.00; H, 5.72;N, 10.84;found: C, 61.73; H, 7.72; N, 10.66. 28

Yield: 44%. ¹H NMR (500 MHz, CDCl₃) δ:11.80 (1H, br s), 8.61 (1H, t,J=6.7 Hz),7.68 (1H, dd, J=8.6, 5.2 Hz), 7.48 (1H, dd,J=8.4, 2.6 Hz),7.28-7.24 (1H, m), 4.80(2H, d, J=7.0 Hz), 4.00-3.94 (4H, m), 2.90(6H,s), 2.24-2.18 (2H, m), 2.06-2.00 (2H,m), 1.96-1.80 (4H, m). HRMS (M + H)calcdfor C₂₁H₂₆FN₄O₆S: 481.1557; found:481.1561. Anal cald forC₂₁H₂₅FN₄O₆S.0.35 CF₃CO₂H. 0.1 C₄H₁₀O: C, 50.29; H,5.03; N, 10.61;found: C, 50.06; H, 4.70; N, 10.51. 29

Yield: 51%. ¹H NMR (500 MHz, CDCl₃) δ:11.84 (1H, s), 8.67 (1H, t, J=5.8Hz), 8.39(1H, s), 8.13 (s, 1H), 7.42 (1H, dd, J=8.4,2.9 Hz) 7.34 (1H,dd, J=8.7, 4.2 Hz), 7.16(1H, td, J=8.1, 2.8 Hz), 4.42 (2H, d, J=6.7 Hz),4.02-3.96 (4H, m), 2.28-2.22 (2H,m), 2.10-2.05 (2H, m), 1.94-1.88 (4H,m).HRMS (M + H) calcd for C₂₁H₂₂FN₆O₄:441.1687; found: 441.1697. Analcald forC₂₁H₂₁FN₆O₄: C, 57.26; H, 4.80; N, 19.08;found: C, 57.27; H,4.85; N, 19.07. 30

Yield: 87%. ¹H NMR (500 MHz, CDCl₃) δ:11.92 (1H, s), 7.41 (1H, br t),7.20-7.17(2H, m), 7.03-7.00 (2H, m), 4.01-3.99 (2H,m), 3.96-3.94 (2H,m),3.68 (2H, q, J=6.7 Hz),2.89 (2H, t, J=6.7 Hz), 2.06-1.97 (4H,m),1.88-1.80 (2H, m), 1.77-1.69 (2H, m).HRMS (M + H) calcd forC₂₀H₂₃FN₃O₄:388.1673; found: 388.1680. Anal cald forC₂₀H₂₂FN₃O₄.0.8 H₂O:C, 60.05; H, 5.90;N, 10.50; found: 0, 60.14; H, 5.60; N, 10.51. 31

Yield: 80%. ¹H NMR (500 MHz, CDCl₃) δ:12.03 (1H, s), 7.44 (1H, br t),7.16-7.13(2H, m), 6.99-6.95 (2H, m), 4.03-4.01 (2H,m), 3.98-3.96 (2H,m), 3.44 (2H, q, J=6.7 Hz),2.68 (2H, t, J=7.6 Hz), 2.18-2.06 (4H,m),1.97-1.84 (6H, m). HRMS (M + H) calcdfor C₂₁H₂₅FN₃O₄: 402.1829;found:402.1840. Anal cald for C₂₁H₂₄FN₃O₄: C,62.83; H, 6.02; N, 10.46;found: C, 62.46;H, 6.26; N, 10.52. 32

Yield: 73%. ¹H NMR (500 MHz, CDCl₃) δ:12.10 (1H, s), 8.55 (1H, t, J=6.4Hz), 8.29(1H, s), 7.68 (1H, dd, J=8.6, 6.1Hz), 7.17(1H, td, J=8.6, 2.8Hz), 7.08 (1H, dd, J=8.6, 2.8 Hz), 4.47 (2H, d, J=6.7 Hz), 4.02-4.00(2H, m), 3.96-3.94 (2H, m), 2.52 (3H,s), 2.23-2.16 (2H, m), 2.09-2.04(2H, m),1.88-1.83 (4H, m). HRMS (M + H) calcd forC₂₂H₂₄FN₆O₄: 455.1843;found: 455.1850.Anal cald for C₂₂H₂₃FN₆O₄: C, 58.14; H,5.10; N, 18.49;found: C, 58.04; H, 4.98; N, 18.53. 33

Yield: 10%. ¹H-NMR (300 MHz, CDCl₃) δ:11.95 (1H, s), 8.84-8.79 (1H, m),8.41 (1H,s), 8.11 (1H, s), 7.68 (1H, dd, J=6.8, 2.0 Hz),7.51-7.42 (2H,m), 7.33 (1H, dd, J=7.3, 1.8 Hz), 4.44 (2H, d, J=7.0 Hz), 3.99-3.92 (4H,m), 2.27-2.18 (2H, m), 2.08-2.00(2H, m), 1.92-1.85 (4H, m). HRMS [M +H]⁺calcd for C₂₁H₂₃N₆O₄: 423.1781; found:423.1773. 34

Yield: 59% yield. ¹H-NMR (300 MHz,CDCl₃) δ: 11.83 (1H, br s), 8.26-8.22(1H,m), 7.43 (1H, dd, J=8.8, 6,2 Hz), 7.15 (1H,dd, J=9.1,2.6 Hz), 7.04(1H, dt, J=8.2,2.6 Hz), 4.91 (1H, dd, J=14.1, 9.0 Hz),4.34 (1H, dd,J=14.3, 3.7 Hz), 3.99-3.89(4H, m), 3.86-3.77 (1H, m), 3.44-3.36 (1H,m),3.23-3.19 (2H, m), 2.40-2.30 (2H, m),2.21-2.10 (2H, m), 2.01-1.89 (4H,m), 1.83-1.74 (4H, m). HRMS [M + H]⁺ calcd forC₂₃H₂₈N₄O₆FS: 507.1714;found: 507.1735.Anal cald for C₂₃H₂₇N₄O₆FS: C, 54.54; H,5.37; N, 11.06;S, 6.33; F, 3.75; found: C,54.27; H, 5.22; N, 11.01; S, 6.14; F, 3.81.35

Yield: 81% yield. ¹H-NMR (300 MHz,CDCl₃) δ: 12.08 (1H, s), 8.27-8.23(1H, m),7.46-7.41 (2H, m), 7.35-7.32 (2H, m), 4.93(1H, dd, J=14.1, 9.0Hz), 4.40 (1H, dd, J=14.1, 3.5 Hz), 4.00-3.96 (2H, m), 3.93-3.88(2H, m),3.86-3.81 (1H, m), 3.44-3.36 (1H,m), 3.22-3.18 (2H, m), 2.41-2.28 (2H,m),2.21-2.11 (2H, m), 2.02-1.89 (4H, m), 1.84-1.74 (4H, m). HRMS [M +H]⁺ calcd forC₂₃H₂₉N₄O₆S: 489.1808; found: 489.1801.Anal cald forC₂₃H₂₈N₄O₆S: C, 56.54; H,5.78; N, 11.47; found: C, 56.63; H, 5.48; N,11.37. 36

Yield: 65%. ¹H NMR (500 MHz, CDCl₃) δ:12.10 (1H, s), 7.74 (1H, br t),7.30 (2H, dd,J=8.5, 5.2 Hz), 7.04 (2H, t, J=8.5 Hz),4.62-4.53 (2H, m),4.14-3.99 (8H, m), 2.51-2.45 (1H, m), 2.36-2.31 (1H, m). HRMS(M + H)calcd for C₁₈H₁₉FN₃O₅:; found:.Anal cald for C₁₈H₁₈FN₃O₅: C, 57.59;H,4.83; N, 11.19; F, 5.06; found: C, 57.95; H,4.96; N, 10.95; F, 5.43.37

Yield: 68%. ¹H NMR (500 MHz, CDCl₃) δ:12.13 (1H, s), 7.71 (1H, br t),7.14-7.08 (2H,m), 6.97 (1H, t, J=8.8 Hz), 4.57-4.49 (2H,m), 4.14-3.99(8H, m), 2.51-2.44 (1H, m),2.36-2.31 (1H, m), 2.27 (3H, s). HRMS(M + H)calcd for C₁₉H₂₁FN₃O₅: 390.1465;found: 390.1451. Anal caldforC₁₉H₂₀FN₃O₅: C, 58.60; H, 5.17; N, 10.79;F, 4.87; found: C, 58.62; H,5.36; N, 10.77;F, 4.95. 38

Yield: 52%. ¹H NMR (500 MHz, CDCl₃) δ:11.908 (1H, s), 8.92 (1H, br t),8.43 (1H, s),8.26 (1H, s), 7.69 (1H, dd, J=8.5, 5.8 Hz),7.21 (1H, td,J=8.2, 2.4 Hz), 7.10 (1H, dd,J=8.5, 2.4 Hz), 4.51-4.35 (2H, m),4.26-3.97 (8H, m), 2.59-2.53 (1H, m), 2.36-2.31(1H, m). HRMS (M + H)calcd forC₂₀H₂₀FN₆O₅: 443.1479; found: 443.1495.Anal caldfor C₂₀H₁₉FN₆O₅: C, 54.29; H,4.32; N, 18.99; F, 4.29; found: C, 54.26;H,4.44; N, 19.01; F, 4.38. 39

Yield: 63%. ¹H NMR (500 MHz, CDCl₃) δ:12.01 (1H, s), 8.03 (1H, br t),7.30-7.24(1H, m), 6.99-6.94 (1H, m), 6.87-6.81 (1H,m), 4.64-4.59 (2H,m), 4.14-3.99 (8H, m),2.55-2.51 (1H, m), 2.51 (3H, s), 2.38-2.31(1H, m).HRMS (M + H) calcd forC₁₉H₂₁FN₃O₅S: 422.1186; found: 422.1165.Anal caldfor C₁₉H₂₁FN₃O₅S: C, 54.14; H,4.78; N, 9.97; found: C, 54.22; H, 5.07;N, 9.90. 40

Yield: 28%. ¹H-NMR (500 MHz, CDCl₃) δ:12.07 (1H, s), 7.81 (1H, t, J=6.0Hz), 7.32(2H, dd, J=8.5, 5.5 Hz), 7.06 (2H, t, J=8.7 Hz), 4.58 (2H, d,J=6.4 Hz), 4.05-4.01(4H, m), 3.84 (2H, dd, J=11.4, 5.3 Hz),3.77 (2H, t,J=11.3 Hz), 2.30 (2H, dt, J=13.3, 5.2 Hz), 1.79 (2H, d, J=13.7 Hz).).HRMS [M + H] calcd for C₁₉H₂₁N₃O₅F:390.14653; found: 390.1465. Analclad forC₁₉H₂₀N₃O₅F: C, 58.60; H, 5.17; N, 10.79;F, 4.87; found: 0,58.70; H, 5.26; N, 10.80;F, 4.99. 41

Yield: 30%. ¹H-NMR (500 MHz, CDCl₃) δ:11.86 (1H, s), 9.12 (1H, t, J=5.6Hz), 8.46(1H, s), 8.39 (1H, s), 7.68 (1H, dd, J=8.2,6.1 Hz), 7.21 (1H,dt, J=8.2, 2.1 Hz), 7.10(1H, dd, J=8.4, 2.0 Hz), 4.45 (2H, dd, J=6.7Hz), 4.02 (4H, s), 3.90 (2H, dd, J=11.3, 4.6 Hz), 3.79 (2H, t, J=11.7Hz),2.44 (2H, dt, J=13.1, 4.9 Hz), 1.80 (2H, d,J=13.4 Hz). HRMS (M + H)calcd forC₂₁H₂₂N₆O₅F: 457.16358; found: 457.1639.Anal cald forC₂₁H₂₁N₆O₅F: C, 55.26; H,4.63; N, 18.41; F, 4.16; found: C, 54.99;H,4.54; N, 18.38; F, 4.08. 42

Yield: 53%. ¹H-NMR (500 MHz, CDCl₃) δ:12.12 (1H, s), 8.25-8.23 (1H, m),7.48 (1H,q, J=8.5, 6.1 Hz), 7.21 (1H, dd, J=9.0,2.6 Hz), 7.08 (1H, dt,J=8.2, 2.5 Hz), 4.90(1H, dd, J=14.2, 8.4 Hz), 4.43 (1H, dd, J=14.0, 4.3Hz), 4.01 (4H, s), 3.86-3.71 (4H,m), 3.45-3.42 (1H, m), 3.32 (1H, dt,J=13.2, 4.4 Hz), 3.28-3.22 (1H, m), 2.47-2.29(4H, m), 2.00-1.93 (2H,m), 1.72 (2H, t, J=15.2 Hz). HRMS [M + H]⁺ calcd forC₂₃H₂₈N₆O₇FS:523.1663; found: 523.1666.Anal cald for C₂₃H₂₇N₆O₇FS.0.5 H₂0: C,51.97;H, 5.31; N, 10.54; F, 3.57; S, 6.03;found: C, 51.84; H, 4.96; N, 10.28;F, 3.62;S, 6.01. 43

Yield: 65%. ¹H-NMR (300 MHz,CDCl₃/1drop MeOD) δ: 8.28-8.24 (1H,m),7.46-7.43 (2H, m), 7.35-7.32 (2H, m), 4.89(1H, dd, J=14.3, 8.4 Hz),4.45 (1H, dd, J=14.3, 4.4 Hz), 3.97 (4H, s), 3.89-3.65 (5H,m), 3.43-3.36(1H, m), 3.33-3.16 (2H, m),2.46-2.24 (4H, m), 1.96-1.88 (2H, m),1.73-1.65 (2H, m). HRMS [M + H]⁺ calcd forC₂₃H₂₉N₄O₇S: 505.1757; found:505.1761.Anal cald for C₂₃H₂₈N₄O₇S: C, 54.75; H,5.59; N, 11.10; S, 6.35;found: C, 55.03; H,5.29; N, 11.06; S, 6.18. 44

Yield: 70%. ¹H-NMR (300 MHz, CDCl₃) δ:11.80 (1H, s), 8.50 (1H, t, J=6.6Hz), 7.74(1H, dd J=8.1, 2.9 Hz), 7.65 (1H, dd, J=8.6, 5.3 Hz), 7.31 (1H,dt, J=8.0, 3.2 H),4.82 (2H, d, J=6.9 Hz), 3.99 (4H, s), 3.84(2H, dd,J=11.5, 4.9 Hz), 3.74 (2H, td, J=11.6, 1.3 Hz), 3.18 (3H, s), 2.31 (2H,td, J=13.2, 5.5 Hz), 1.74 (2H, d, J=13.2 Hz).HRMS [M + H]⁺ calcd forC₂₀H₂₃N₃O₇SF:468.1241; found: 468.1237. Anal cald forC₂₀H₂₂N₃O₇SF: C,51.38; H, 4.74; N, 8.98;S, 6.86; F, 4.06; found: C, 51.25; H, 4.62;N,8.81; S, 6.82; F, 4.18. 45

Yield: 19%. ¹H-NMR (300 MHz, CDCl₃) δ:12.08 (1H, s), 7.75 (1H, s, J=5.8Hz),7.15-7.08 (2H, m), 6.96 (1H, t, J=9.0 Hz),4.51 (2H, d, J=6.2 Hz),4.00 (4H, s), 3.85-3.70 (4H, m), 2.32-2.22 (2H, m), 2.26 (3H,d, J=1.8Hz), 1.76 (2H, d, J=13.5 Hz).HRMS [M + H]⁺ calcd forC₂₀H₂₃N₃O₅F:404.1622; found: 404.1615. 46

Yield: 39%. ¹H-NMR (300 MHz, CDCl₃) δ:12.18 (1H, s), 8.12 (1H, t, J=6.0Hz), 7.19(1H, d, J=8.0 Hz), 6.48-6.41 (2H, m), 4.50(2H, d, J=6.2 Hz),3.99 (3H, s), 3.88 (3H,s), 3.86-3.71 (4H, m), 3.78 (4H, s), 2.27(2H, td,J=13.0, 5.6 Hz), 1.76 (2H, d, J=12.8 Hz). HRMS [M + H]⁺ calcdforC₂₁H₂₆N₃O₇: 432.1771; found: 432.1771.Anal cald for C₂₁H₂₅N₃O₇: C,58.46; H,5.84; N, 9.74; found: C, 58.22; H, 5.89; N, 9.69. 47

Yield: 44%. ¹H-NMR (300 MHz, CDCl₃) δ:11.91 (1H, s), 8.52 (1H, t, J=6.6Hz), 7.63(1H, dd, J=8.4, 5.5 Hz), 7.47 (1H, dd, J=8.4, 2.9 Hz),7.27-7.22 (1H, m), 4.81 (2H, d,J=6.9 Hz), 3.98 (4H, s), 3.85-3.70 (4H,m),2.90 (6H, s), 2.31 (2H, td, J=13.0, 5.2 Hz),1.73 (2H, d, J=13.5 Hz).HRMS [M + H]⁺calcd for C₂₁H₂₆N₄O₇FS: 497.1506; found:497.1497. Anal caldfor C₂₁H₂₅N₄O₇FS: C,50.80; H, 5.07; N, 11.28; S, 6.45; F, 3.82;found: C,50.59; H, 4.99; N, 11.01; S, 6.19;F, 4.03. 48

Yield: 54%. ¹H-NMR (500 MHz, CDCl₃) δ:12.20 (1H, s), 7.76 (1H, t, J=5.3Hz), 7.14-7.11 (2H, m), 7.08 (1H, d, J=7.6 Hz), 4.54(2H, d, J=6.1 Hz),4.04-4.01 (4H, m), 3.83(2H, dd, J=11.4, 5.0 Hz), 3,77 (2H, t, J=11.4Hz), 2.32-2.28 (2H, m), 2.26 (6H, d, J=5.8 Hz), 1.78 (2H, d, J=13.4 Hz).HRMS[M + H]⁺ calcd for C₂₁H₂₆N₃O₅: 400.1872;found: 400.1869. Anal caldfor C₂₁H₂₅N₃O₅C, 63.14; H, 6.30; N, 10.52; found: C,62.39; H, 6.01; N,10.23. 49

Yield: 59%. ¹H-NMR (300 MHz, CDCl₃) δ:11.80 (1H, s), 8.83 (1H, t, J=6.2Hz) 8.20(1H, s), 7.63 (1H, dd, J=8.6, 6.0 Hz), 7.20(1H, dd, J=8.6, 2.4Hz), 6.99 (1H, dd, J8.4, 2.6 Hz), 4.27 (2H, d, J=6.6 Hz), 3.99(4H, s),3.87 (2H, dd, J=11.3, 4.4 Hz),3.76 (2H, t, J=11.7 Hz), 2.45 (3H, s),2.48-2.38 (2H, m), 1.78 (2H, d, J=13.5 Hz).HRMS [M + H]⁺ calcd forC₂₂H₂₄N₆O₅F:471.1792; found: 471.1786. Anal cald forC₂₂H₂₃N₆O₅F: C,56.16; H, 4.92; N, 17.86;F, 4.03; found: C, 55.88; H, 5.02; N, 17.74;F,3.79. 50

Yield: 35%. ¹H-NMR (300 MHz, CDCl₃) δ:12.11 (1H, s), 8.78 (1H, t, J=7.3Hz), 8.28(1H, s), 7.66 (1H, dd, J=8.6, 6.0 Hz), 7.14(1H, td, J=8.2, 2.7Hz), 7.06 (1H, dd, J=8.4, 2.6 Hz), 4.45 (2H, d, J=6.6 Hz), 3.99(4H, s),3.82-3.71 (4H, m), 2.59 (3H, s),2.39-2.29 (2H, m), 1.75 (2H, d, J=14.3Hz).HRMS (M + H) calcd for C₂₂H₂₄N₆O₅F:471.1792; found: 471.1812. Analcald forC₂₂H₂₄N₆O₅F.0.2 H₂O: C, 55.74; H, 4.98;N, 17.73; F, 4.01; found:C, 55.60; H, 4.92;N, 17.85; F, 3.84. 51

Yield: 34%. ¹H NMR (500 MHz, CDCl₃) δ:12.01 (1H, s), 8.95 (1H, t, J=6.3Hz), 8.46(1H, s), 8.15 (1H, s), 7.73 (1H, dd, J=8.6,6.1 Hz), 7.21 (1H,td, J=8.2, 2.6 Hz), 7.12(1H, dd, J=8.6, 2.4 Hz), 4.47 (2H, d, J=6.7 Hz),3.96 (4H, s), 2.67-2.75 (2H, m),2.32-2.40 (2H, m), 2.15-2.24 (1H, m),2.08(1H, m). HRMS (M + H) calcd forC₂₀H₂₀N₆O₄F: 427.1530; found:427.1540. 52

Yield: 27%. ¹H NMR (500 MHz, CDCl₃) δ:12.00 (1H, s), 7.82-7.90 (1H, m),7.32 (2H,dd, 9, 5 Hz), 7.02-7.08 (2H, m), 4.61 (2H, d,6 Hz), 3.97 (4H,ddd, 14, 8, 3 Hz), 2.60-2.66 (2H, m), 2.29-2.36 (2H, m), 2.01-2.10(1H,m), 1.90-1.99 (1H, m). ¹³C NMR (126 MHz,CDCl₃) δ: 168.39, 163.46,161.50,157.66, 150.60, 146.85, 133.20, 133.17,129.42, 129.36, 125.40,116.02, 115.84,78.73, 58.62, 42.53, 34.74, 14.13. HRMS(M + H) calcd forC₁₈H₁₉N₃O₃F: 360.1360;found: 360.1350. 53

Yield: 43%. ¹H NMR (500 MHz, CDCl₃) δ:11.81 (1H, s), 8.68 (1H, t, J=7Hz), 7.71-7.77 (2H, m), 7.35 (1H, td, 8, 3 Hz), 4.84(2H, d, 7 Hz),3.93-3.95 (4H, m), 3.18 (3H,s), 2.62-2.68 (2H, m), 2.29-2.36 (2H,m),2.13-2.19 (1H, m), 2.01-2.08 (1H, m). ¹³CNMR (126 MHz, CDCl₃) δ:168.22, 163.16,161.14, 157.70, 150.86, 146.63, 140.77,140.72, 135.31,135.25, 132.83, 132.80,125.57, 121.69, 121.53, 117.65, 117.45,78.69,58.51, 45.18, 42.53, 40.34, 34.84,13.59. HRMS (M + H) calcdforC₁₉H₂₁FN₃O₆S: 438.1135, found 438.1149. 54

Yield: 56%. ¹H NMR (500 MHz, CDCl₃) δ:11.91 (1H, s), 8.73 (1H, t, J=6.7Hz), 7.71(1H, dd, J=8.4, 5.3 Hz), 7.49 (1H, dd, J=8.4, 2.6 Hz),7.25-7.29 (1H, m), 4.83 (2H, d,J=7.0 Hz), 3.94 (4H, s), 2.90 (6H, s),2.64-2.70 (2H, m), 2.28-2.35 (2H, m), 2.12-2.21(1H, m), 1.99-2.08 (1H,m). ¹³C NMR (126 MHz,CDCl₃) δ: 168.09, 162.72, 160.72,157.75, 150.67,146.59, 138.58, 138.53,135.31, 135.25, 132.70, 132.67, 125.73,120.40,120.23, 116.86, 116.66, 78.74,58.53, 42.50, 40.34, 37.61, 34.81,13.58.HRMS (M + H) calcd for C₂₀H₂₄N₄O₆FS467.1401, found 467.1418. Anal.calcd forC₂₀H₂₃N₄O₆FS: C 51.49, H 4.97, N 12.01, F4.07, S 6.87; found: C51.27, H 4.98, N12.17, F 4.11, S 6.86. 55

Yield: 73%. ¹H NMR (500 MHz, CDCl₃) δ:12.16 (1H, s), 8.33-8.39 (1H, m),7.49 (1H,dd, J=8.7, 6.3 Hz), 7.17 (1H, dd, J=9.0,2.6 Hz), 7.07 (1H, td,J=8.2, 2.6 Hz), 4.97(1H, dd, J=14.0, 8.9 Hz), 4.40 (1H, dd, J=14.3, 3.7Hz), 3.92-3.98 (4H, m), 3.81-3.88(1H, m), 3.44 (1H, dt, J=12.6, 3.6Hz),3.23-3.28 (2H, m), 2.64-2.70 (2H, m), 2.32-2.42 (2H, m),2.20-2.29 (2H, m), 1.98-2.06(2H, m), 1.88-1.98 (2H, m). ¹³C NMR (126MHz,CDCl₃) δ: 168.28, 163.49, 161.50,157.79, 150.47, 146.69, 139.89,139.82,133.17, 132.16, 132.08, 125.81, 116.64,116.47, 115.15, 114.97,79.12, 58.57,54.17, 51.07, 42.54, 38.53, 34.58, 34.52,24.97, 24.24,14.00. HRMS (M + H) calcdfor C₂₂H₂₆N₄O₆FS 493.1557; found493.1549. Anal.calcd for C₂₂H₂₅N₄O₆FS: C53.65, H 5.12, N 11.38, F 3.86, S 6.51;found: C53.73, H 4.91, N 11.06, F 3.55, S 6.42. 56

Yield: 66%. ¹H NMR (500 MHz, CDCl₃) δ:12.15-12.29 (1H, br s), 8.32-8.40(1H, m),7.47-7.52 (1H, m), 7.42-7.47 (1H, m), 7.33-7.39 (2H, m), 4.99(1H, dd, J=14.0, 8.9 Hz),4.47 (1H, dd, J=14.3, 3.7 Hz), 3.92-3.98 (4H,m), 3.84-3.92 (1H, m), 3.41-3.47(1H, m), 3.22-3.28 (2H, m), 2.64-2.71(2H,m), 2.37-2.46 (1H, m), 2.31-2.37 (1H, m),2.19-2.29 (2H,m), 1.98-2.06 (2H, m), 1.89-1.98 (2H, m). ¹³C NMR (126 MHz, CDCl₃)δ:168.26, 157.82, 150.40, 146.68, 138.82,137.01, 130.80, 129.46, 129.32,127.72,125.90, 79.15, 58.58, 54.15, 51.05, 42.53,39.17, 34.58, 34.51,25.05, 24.34, 14.03.HRMS (M + H) calcd for C₂₂H₂₇N₄O₆S475.1651; found475.1665. Anal. calcd forC₂₂H₂₆N₄O₆S: C 55.68, H 5.52, N 11.81, S6.76;found: C 55.53, H 5.36, N 11.77, S 6.61. 57

Yield: 55%. ¹H NMR (500 MHz, CDCl₃) δ:11.93 (1H, s), 8.61 (1H, br), 7.98(1H, s),7.70 (1H, dd, J=8.5, 5.8 Hz), 7.22-7.26(1H, m), 7.02 (1H, dd,J=8.4, 2.6 Hz), 4.32(2H, d, J=6.7 Hz), 3.94-3.97 (4H, m), 2.72(2H, ddd,J=12.7, 9.2, 5.5 Hz), 2.48 (3H,s), 2.36 (2H, ddd, J=12.5, 10.1, 7.3Hz),2.15-2.23 (1H, m), 2.05-2.14 (1H, m). ¹³CNMR (126 MHz, CDCl₃)δ: 168.13, 163.04,161.04, 157.64, 153.70, 151.42, 150.47,146.83, 137.25,137.17, 133.57, 133.50,130.89, 130.86, 125.58, 117.61, 117.45,114.43,114.24, 78.78, 65.84, 58.62, 42.44,38.82, 34.75, 15.29, 13.83, 12.68.HRMS(M + H) calcd for C₂₁H₂₂N₆O₄F: 441.1687;found: 441.1692. 58

Yield: 43%. ¹H NMR (500 MHz, CDCl₃) δ:11.90 (1H, br s), 8.62 (1H, t, 6.7Hz), 7.74(1H, dd, J=7.9, 2.8 Hz), 7.71 (1H, dd, J=8.6, 5.2 Hz), 7.34(1H, dt, J=8.0, 2.6 Hz),4.83 (2H, d, J=6.7 Hz), 4.36 (2H, br), 3.89(2H,t, J=5.7 Hz), 3.17 (3H, s), 2.69-2.79(2H, br), 2.37-2.46 (2H, m),1.85-1.94 (1H,m), 1.79- .85 (2H, m), 1.63-1.73 (1H, m).¹³C NMR (125.77MHz, CDCl₃) δ: 168.34,163.12, 161.11, 158.52, 151.12, 147.55,140.72,140.67, 135.12, 135.05, 132.86,132.83, 124.42, 121.66, 121.49,117.61,117.41, 82.32, 64.43, 45.17, 40.80, 40.25,32.02, 28.59, 12.79.HRMS (M + H) calcdfor C₂₀H₂₃FN₃O₆S: 452.1292, found452.1299. 59

Yield: 52%. ¹H NMR (500 MHz, CDCl₃) δ:12.09 (1H, s), 7.82 (1H, br t),7.31 (2H, dd,J=8.1, 5.6 Hz), 7.05 (2H, t, J=8.5 Hz),4.59 (2H, d,J=6.1Hz), 4.39 (2H, br), 3.92(2H, t, J=5.5 Hz), 2.63-2.71 (2H, br),2.38-2.46 (2H, m), 1.89 (1H, td, J=10.0, 5.6 Hz),1.82-1.87 (2H, m),1.60-1.69 (1H, m).¹³C NMR (126 MHz, CDCl₃) δ: 168.48,163.46, 161.49,158.45, 150.94, 147.73,133.15, 133.12, 129.45, 129.39, 124.27,115.99,115.83, 82.11, 64.59, 42.49, 40.81,31.88, 28.67, 12.85. HRMS (M + H)calcdfor C₁₉H₂₁FN₃O₄: 374.1516; found:374.1515. 60

Yield: 18%. ¹H NMR (500 MHz, CDCl₃) δ:12.10 (1H, s), 9.02 (1H, t, J=6.4Hz), 8.46(1H, s), 8.13 (1H, s), 7.71 (1H, dd, J=8.5,5.8 Hz), 7.21 (1H,td, J=8.2, 2.7 Hz), 7.11(1H, dd, J=8.4, 2.6 Hz), 4.45 (2H, d, J=7.0 Hz),4.38 (2H, br), 3.89 (2H, t, J=5.6 Hz),2.82 (2H, br), 2.41-2.48 (2H, m),1.87-1.95 (1H, m), 1.83 (2H, ddd, J=10.8, 5.6,5.5 Hz), 1.69-1.78 (1H,m). ¹³C NMR (126 MHz,CDCl₃) δ: 168.10, 163.20, 161.20,158.53, 152.73,150.74, 147.62, 143.85,136.97, 136.89, 134.46, 134.38, 128.65,128.61,124.63, 117.14, 116.98, 112.38,112.19, 82.35, 64.46, 40.71, 39.11,32.10,28.61, 12.71. HRMS (M + H) calcd forC₂₁H₂₂FN₆O₄: 441.1687, found:441.1695. 61

Yield: 33%. ¹H NMR (500 MHz, CDCl₃) δ:12.02 (1H, br s), 8.64 (1H, t,J=6.6 Hz),7.69 (1H, dd, J=8.5, 5.5 Hz), 7.49 (1H, dd,J=8.2, 2.7 Hz),7.24-7.29 (1H, m), 4.82(2H, d, J=6.7 Hz), 4.36 (2H, br), 3.88 (2H,t,J=5.5 Hz), 2.89 (6H, s), 2.74 (2H, m),2.37-2.44 (2H, m), 1.85-1.92 (1H,m), 1.82(2H, dt, J=11.0, 5.5 Hz), 1.65-1.74 (1H,m). ¹³C NMR (126 MHz,CDCl₃) δ: 168.21,162.69, 160.68, 158.54, 150.96, 147.55,138.56, 138.50,135.15, 135.09, 132.72,132.69, 124.57, 120.38, 120.22, 116.84,116.64,82.37, 64.39, 40.71, 40.22, 37.58,32.09, 28.59, 12.77. HRMS (M + H)calcdfor C₂₁H₂₆FN₄O₆FS 481.1557, found481.1555. Anal. calcd forC₂₁H₂₅N₄O₆FS: C52.49, H 5.24, N 11.66, F 3.95, S 6.67;found: C 52.22, H5.09, N 11.43, F 3.93, S 6.60. 62

Yield: 82%. ¹H NMR (500 MHz, CDCl₃) δ:11.90 (1H, s), 8.03 (1H, br t),7.40-7.30(5H, m), 4.67 (2H, d, J=6.4 Hz), 3.96 (2H,t, J=6.4 Hz),2.63-2.57 (2H, m), 2.07-1.91(8H, m). HRMS (M + H) calcd forC₁₉H₂₂N₃O₃:340.1661; found: 340.1652.Anal cald for C₁₉H₂₁N₃O₃: C, 67.24; H,6.23; N,12.38; found: C, 66.85; H, 6.14; N, 12.31. 63

Yield: 78%. ¹H NMR (500 MHz, CDCl₃) δ:11.93 (1H, s), 7.99 (1H, br t),7.25 (2H, d, J=6.7 Hz), 7.18 (2H, d, J=7.6 Hz), 4.62(2H, d, J=6.1 Hz),3.96 (2H, t, J=6.3 Hz),2.62-2.56 (2H, m), 2.35 (3H, s), 2.07-1.90(8H,m). HRMS (M + H) calcd forC₂₀H₂₄N₃O₃: 354.1818; found: 354.1823.Analcald for C₂₀H₂₃N₃O₃: C, 67.97; H,6.55; N, 11.89; found: C, 67.81; H,6.84; N, 11.94. 64

Yield: 76%. ¹H NMR (500 MHz, CDCl₃) δ:11.93 (1H, s), 7.96 (1H, t, J=5.2Hz), 7.29(2H, d, J=8.5 Hz), 6.90 (2H, d, J=8.5 Hz),4.59 (2H, d, J=6.6Hz), 3.96 (2H, t, J=6.4 Hz),3.81 (3H, s) 2.62-2.56 (2H, m), 2.07-1.90(8H, m). HRMS (M + H) calcd forC₂₀H₂₄N₃O₃: 370.1767; found:370.1780.Anal cald for C₂₀H₂₃N₃O₃: C, 65.02; H,6.27; N, 11.37; found: C,64.94; H, 6.53; N, 11.46. 65

Yield: 74%. ¹H NMR (500 MHz, CDCl₃) δ:11.79 (1H, s), 8.02 (1H, br t),7.34 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=8.6 Hz), 4.63(2H, d, J=6.4 Hz),3.96 (2H, t, J=6.4 Hz),2.63-2.57 (2H, m), 2.08-1.91 (8H, m).HRMS (M + H)calcd for C₁₉H₂₁ClN₃O₃:374.1271; found: 374.1287. Anal caldforC₁₉H₂₀ClN₃O₃: C, 61.04; H, 5.39; N, 11.24;found: C, 61.05; H, 5.41;N, 11.10. 66

Yield: 72%. ¹H NMR (500 MHz, CDCl₃) δ:11.83 (1H, s), 8.01 (1H, br t),7.34 (2H, dd,J=8.6, 5.2 Hz), 7.06 (2H, t, J=8.6 Hz),4.62 (2H, d, J=6.4Hz), 3.96 (2H, t, J=6.3 Hz),2.62-2.56 (2H, m), 2.08-1.91 (8H, m).HRMS(M + H) calcd for C₁₉H₂₁FN₃O₃:358.1567; found: 358.1551. Anal caldforC₁₉H₂₀FN₃O₃: C, 63.85; H, 5.64; N, 11.75;found: C, 63.72; H, 5.52; N,11.63. 67

Yield: 80%. ¹H NMR (500 MHz, CDCl₃) δ:11.78 (1H, s), 8.06 (1H, br t),7.36-7.31(1H, m), 7.14 (1H, d, J=7.9 Hz), 7.06 (1H,d, J=9.5 Hz), 7.00(1H, td, J=8.4, 2.4 Hz),4.66 (2H, d, J=6.4 Hz), 3.97 (2H, t, J=6.4 Hz),2.64-2.58 (2H, m), 2.09-1.91(8H, m). HRMS (M + H) calcd forC₁₉H₂₁FN₃O₃:358.1567; found: 358.1553.Anal cald for C₁₉H₂₀FN₃O₃: C, 63.85; H,5.64;N, 11.75; found: C, 63.86; H, 5.64; N, 11.50. 68

Yield: 75%. ¹H NMR (500 MHz, CDCl₃) δ:11.78 (1H, s), 8.14 (1H, br t),7.40 (1H, td, J=7.5, 1.2 Hz), 7.32-7.28 (1H, m), 7.14 (1H,td, J=7.5, 1.0Hz), 7.09 (1H, dd, J=10.1,8.2 Hz), 4.70 (2H, d, J=6.4 Hz), 3.95 (2H,t,J=6.4 Hz), 2.65-2.59 (2H, m), 2.09-1.90(8H, m). HRMS (M + H) calcdforC₁₉H₂₁FN₃O₃: 358.1567; found: 358.1569.Anal cald for C₁₉H₂₀FN₃O₃: C,63.85; H,5.64; N, 11.75; found: C, 63.75; H, 5.55; N, 11.70. 69

Yield: 71%. ¹H NMR (500 MHz, CDCl₃) δ:11.95 (1H, s), 7.99 (1H, br t),7.14 (1H, d, J=7.6 Hz),7.13 (1H, s), 7.09 (1H, d, J=7.6 Hz),4.59 (2H, d,J=6.4 Hz), 3.96 (2H, t, J=6.4 Hz), 2.62-2.57 (2H, m), 2.27 (3H, s),2.26(3H, s), 2.07-1.90 (8H, m). HRMS(M + H) calcd for C₂₁H₂₆N₃O₃:368.1974;found: 368.1960. Anal cald for C₂₁H₂₅N₃O₃:C, 68.64; H, 6.85; N,11.43; found: C,67.93; H, 5.93; N, 11.27. 70

Yield: 91%. ¹H NMR (500 MHz, CDCl₃) δ:11.70 (1H, s), 8.05 (1H, t, J=5.5Hz), 7.44(1H, s), 7.43 (1H, d, J=5.5 Hz), 7.21 (1H,dd, J=8.1, 1.7 Hz),4.61 (2H, d, J=6.4 Hz),3.97 (2H, t, J=6.4 Hz), 2.64-2.58 (2H,m),2.09-1.91 (8H, m). HRMS (M + H) calcdfor C₁₉H₂₀Cl₂N₃O₃: 408.0882;found:408.0871. Anal cald for C₁₉H₁₉Cl₂N₃O₃: C,55.89; H, 4.69; N, 10.29;found: C, 55.65;H, 4.51; N, 10.26. 71

Yield: 81%. ¹H NMR (500 MHz, CDCl₃) δ:11.99 (1H, s), 8.35 (1H, t, J=5.5Hz, 7.23(1H, d, J=8.2 Hz), 6.49 (1H, d, J=2.1 Hz),6.46 (1H, dd, J=8.2,2.1 Hz), 4.55 (2H, d,J=6.4 Hz), 3.94 (2H, t, J=6.4 Hz), 3.88(3H, s),3.80 (3H, s), 2.65-2.59 (2H, m),2.10-1.89 (8H, m). HRMS (M + H) calcdforC₂₁H₂₆N₃O₅: 400.1872; found: 400.1884.Anal cald for C₂₁H₂₅N₃O₅: C,63.14; H,6.30; N, 10.52; found: C, 62.99; H, 6.46; N, 10.49. 72

Yield: 74%. ¹H NMR (500 MHz, CDCl₃) δ:11.86 (1H, s), 7.99 (1H, t, J=4.9Hz), 7.17(1H, d, J=7.0 Hz), 7.15-7.12 (1H, m), 6.99(1H, t, J=8.9 Hz),4.58 (2H, d, J=6.4 Hz),3.96 (2H, t, J=6.4 Hz), 2.63-2.57 (2H, m),2.28(3H, d, J=1.5 Hz), 2.08-1.91 (8H, m).HRMS (M + H) calcd forC₂₀H₂₃FN₃O₃:372.1723; found: 372.1737. Anal cald forC₂₀H₂₂FN₃O₃: C,64.67; H, 5.97; N, 11.31;found: C,64.73; H, 6.20; N, 11.30. 73

Yield: 73%. ¹H NMR (500 MHz, CDCl₃) δ:11.82 (1H, s), 8.02 (1H, br t),7.17 (1H, t, J=7.8 Hz), 7.02 (1H, d, J=8.6 Hz), 7.00(1H, d, J=10.7 Hz),4.61 (2H, d, J=6.1 Hz),3.96 (2H, t, J=6.4 Hz), 2.63-2.57 (2H,m), 2.26(3H, s), 2.08-1.91 (8H, m). HRMS(M + H) calcd for C₂₀H₂₃FN₃O₃:372.1723;found: 372.1714. Anal cald forC₂₀H₂₂FN₃O₃: C, 64.67; H, 5.97;N, 11.31;found: C, 64.56; H, 6.08; N, 11.41. 74

Yield: 73%. ¹H NMR (500 MHz, CDCl₃) δ:11.78 (1H, s), 7.91 (1H, d, J=7.6Hz),7.36-7.33 (2H, m), 7.06 (2H, td, J=8.6, 1.2 Hz),5.25-5.19 (H, m),3.96 (2H, t, J=6.4 Hz),2.64-2.56 (2H, m), 2.11-1.91 (8H, m),1.62 (3H, d,J=7.0 Hz). HRMS (M + H)calcd for C₂₀H₂₃FN₃O₃: 372.1723; found:372.1708.Anal cald for C₂₀H₂₂FN₃O₃: C,64.67; H, 5.97; N, 11.31; found: C,63.20;H, 6.22; N, 10.74. 75

Yield: 79%. ¹H NMR (500 MHz, CDCl₃) δ:11.67 (1H, s), 8.13 (1H, br t),7.11-7.03(2H, m), 6.99-6.94 (1H, m), 4.68 (2H, d, J=6.4 Hz), 3.96 (2H,t, J=6.4 Hz), 2.65-2.59(2H, m), 2.10-1.91 (8H, m). HRMS (M + H)calcd forC₁₉H₂₀F₂N₃O₃: 376.1473; found:376.1483. Anal cald for C₁₉H₁₉F₂N₃O₃:C,60.79; H, 5.10; N, 11.19; found: C, 60.60;H, 5.21; N, 11.17. 76

Yield: 75%. ¹H NMR (500 MHz, CDCl₃) δ:11.62 (1H, s), 8.30 (1H, t, J=5.8Hz), 7.41(1H, d, J=2.5 Hz), 7.34 (1H, d, J=8.6 Hz),7.25 (1H, dd, J=8.2,2.4 Hz), 4.69 (2H, d,J=6.7 Hz), 3.96 (2H, t, J=6.3 Hz), 2.66-2.60 (2H,m), 2.11-1.91 (8H, m). HRMS(M + H) calcd for C₁₉H₂₀Cl₂N₃O₃:408.0882;found: 408.0879. Anal cald forC₁₉H₁₉Cl₂N₃O₃: C, 55.89; H, 4.69;N, 10.29;found: C, 55.66; H, 4.83; N, 10.27. 77

Yield: 51%. ¹H NMR (500 MHz, CDCl₃) δ:11.74 (1H, s), 8.97 (1H, t, J=6.4Hz), 8.41(1H, s), 8.16 (1H, s), 7.44 (1H, dd, J=8.5,2.8 Hz), 7.35 (1H,dd, J=8.5, 4.9 Hz), 7.15(1H, td, J=8.5, 2.8 Hz), 4.46 (2H, d, J=6.7 Hz),3.94 (2H, t, J=6.4 Hz), 2.75-2.69(2H, m), 2.16-1.90 (8H, m). HRMS (M +H)calcd for C₂₁H₂₂FN₆O₃: 425.1737; found:425.1735. Anal cald forC₂₁H₂₁FN₆O₆: C,59.42; H, 4.98; N, 19.80; found: C, 59.20;H, 4.88; N,19.51. 78

Yield: 59%. ¹H NMR (500 MHz, CDCl₃) δ:11.81 (1H, s), 9.07 (1H, t, J=6.4Hz), 8.46(1H, s), 8.18 (1H, s), 7.73 (1H, dd, J=8.4,6.0 Hz), 7.22 (1H,td, J=8.2, 2.4 Hz), 7.12(1H, dd, J=8.6, 2.4 Hz), 4.48 (2H, d, J=6.7 Hz),3.94 (2H, t, J=6.4 Hz), 2.75-2.69(2H, m), 2.17-1.89 (8H, m). HRMS (M +H)calcd for C₂₁H₂₂FN₆O₃: 425.1737; found:425.1727. Anal cald forC₂₁H₂₁FN₆O₆: C,59.42; H, 4.98; N, 19.80; found: C, 59.35;H, 4.69; N,19.85. 79

Yield: 53%. ¹H NMR (500 MHz, CDCl₃) δ:11.96 (1H, s), 8.42 (1H, br t),7.49 (1H, dd,J=8.5, 6.4 Hz), 7.18 (1H, dd, J=9.2, 2.4 Hz),7.08 (1H, td,J=8.2, 2.4 Hz), 4.99(1H, dd, J=14.4, 8.5 Hz), 4.42 (1H, dd, J=14.4, 3.7Hz), 3.99-3.83 (3H, m), 3.45 (1H,dt, J=12.5, 4.0 Hz), 3.28-3.25 (2H,m),2.70-2.61 (2H, m), 2.45-2.31 (2H, m), 2.03-1.9 (10H, m). HRMS (M +H) calcd forC₂₃H₂₈FN₄O₅S: 491.1764; found: 491.1776.Anal cald forC₂₃H₂₇FN₄O₅S: C, 56.31; H,5.54; N, 11.41; found: C, 56.07; H, 5.60; N,11.25. 80

Yield: 66%. ¹H NMR (500 MHz, CDCl₃) δ:11.87 (1H, s), 9.11 (1H, t, J=6.4Hz), 8.45(1H, s), 8.17 (1H, s), 7.73 (1H, dd, J=7.3,1.2 Hz), 7.51 (1H,td, J=7.3, 1.2 Hz), 7.47(1H, td, J=7.6, 1.5 Hz), 7.36 (1H, dd, J=7.6,1.0 Hz), 4.51 (2H, d, J=6.7 Hz), 3.94(2H, t, J=6.4 Hz), 2.76-2.70 (2H,m), 2.17-1.89 (8H, m). HRMS (M + H) calcd forC₂₁H₂₃N₆O₃: 407.1832;found: 407.1833.Anal cald for C₂₁H₂₂N₆O₃: C, 62.05; H,5.45; N, 20.67;found: C, 61.86; H, 5.48; N,20.90. 81

Yield: 57%. ¹H NMR (500 MHz, CDCl₃) δ:11.60 (1H, s), 8.78 (1H, t, J=6.4Hz), 7.76(1H, dd, J=8.2, 2.4 Hz), 7.73 (1H, dd, J=8.6, 5.2 Hz), 7.35(1H, td, J=8.2, 2.8 Hz),4.86 (2H, d, J=7.0 Hz), 3.93 (2H, t, J=6.4Hz),3.19 (3H, s), 2.68-2.62 (2H, m), 2.15-1.88 (8H, m). HRMS (M + H)calcd forC₂₀H₂₃FN₃O₅S: 436.1342; found: 436.1325.Anal cald forC₂₀H₂₂FN₃O₅S: C, 55.16; H,5.09; N, 9.65; found: C, 55.00; H, 4.93; N,9.45. 82

Yield: 64%. ¹H NMR (500 MHz, CDCl₃) δ:11.48 (1H, br s), 8.82 (1H, t,J=6.4 Hz),7.71 (1H, dd, J=8.2, 5.5 Hz), 7.51 (1H, dd,J=8.2, 2.1 Hz),7.29 (1H, J=8.2,2.4 Hz), 4.85 (2H, d, J=7.0 Hz), 3.94 (2H, t, J=6.4 Hz),2.91 (6H, s), 2.69-2.64 (2H, m),2.15-1.89 (8H, m). HRMS (M + H) calcdforC₂₁H₂₆FN₄O₅S: 465.1608; found: 465.1593.Anal cald forC₂₁H₂₅FN₄O₅S.0.44CF₃CO₂H: C, 51.06; H, 4.98; N, 10.89;found: C, 51.41;H, 5.18; N, 10.50. 83

Yield: 48%. ¹H NMR (500 MHz, CDCl₃) δ:12.01 (1H, s), 8.43-8.41 (1H, m),7.50-7.48(1H, m), 7.46-7.45 (1H, m), 7.35-7.35 (2H,m), 5.02 (1H, dd,J=14.3, 8.6 Hz), 4.49(1H, dd, J=14.3, 4.0 Hz), 3.96-3.87 (3H,m),3.46-3.42 (1H, m), 3.27-3.24 (2H, m),2.71-2.61 (2H, m), 2.45-2.31 (2H,m), 2.02-1.84 (10H, m). HRMS (M + H) calcd forC₂₃H₂₉N₄O₅S: 473.1859;found: 473.1866.Anal cald for C₂₃H₂₈N₄O₅S.0.12C₂H₅OH.0.3 H₂O: C, 57.73;H, 6.11; N,11.59; found: C, 57.48; H, 5.67; N, 11.47. 84

Yield = 47%. ¹H NMR (300 MHz, CDCl₃) δ:1.65-2.02 (8 H, m), 2.07 (2 H, t,J=7 Hz),4.03 (2 H, t, J=7 Hz), 4.55 (2 H, d, J=6.2 Hz),7.02 (2 H, t,J=8.6 Hz), 7.29 (2 H, dd, J=8.6, 5.3 Hz), 7.90 (1H, brs), 12.09 (1 H,s).HRMS (M + H) calcd for C₁₉H₂₁FN₃O₃:358.1567; found: 358.1578. 85

Yield: = 54%. ¹H NMR (300 MHz, CDCl₃) δ:1.64 1.78 (4 H, m), 1.87-2.01 (4H, m), 2.07(2 H, t, J=7 Hz), 3.15 (3H, s), 4.01 (2 H, t,J=7 H), 4.82 (2H, d, J=7.0 Hz), 7.32 (1 H,dd, J=7.9, 2.7 Hz), 7.62-7.78 (2 H, m),8.55(1 H, t, J=7.0 Hz), 11.87 (1 H, s).HRMS (M + H) calcd forC₂₀H₂₃FH₃O₅S:436.1342; found 436.1341. 86

Yield = 15%. ¹H NMR (300 MHz, CDCl₃)δ: 1.62-1.79 (4 H, m), 1.86-2.02 (4H, m),2.07 (2 H, t, J=7 Hz), 2.86 (6 H, s), 4.00(2H, t, J=7 Hz), 4.80 (2H, d, J=6.6 Hz),7.19-7.30 (1H, m), 7.50 (1H, dd, =8.4, 2.6 Hz),7.66 (1H,dd, J=8.6, 5.3 Hz), 8.54 (1 H,t, J=6.8 Hz), 12.00 (1H, s). HRMS(M + H)calcd for C₂₁H₂₆FN₄O₅S: 465.1608;found 465.1626. 87

Yield = 13%. ¹H NMR (300 MHz, CDCl₃) δ:1.64-1.83 (4 H, m), 1.87-2.05 (4H, m),1.87-2.05 (4 H, m), 2.09 (2 H, t, J=7 Hz),4.01 (2H, t, J=7 Hz),4.44 (2 H, d, J=6.6 Hz),7.08 (1H, dd, J=8.4, 2.5 Hz), 7.19 (1H, dt,J=8.4, 2.5 Hz), 7.67 (1 H, dd, J=8.4, 5.9 Hz), 8.15 (1H, s), 8.42 (1H,s),8.77 (1H, t, J=6.8 Hz), 12.02 (1H, s).HRMS (M + H) calcd forC₂₁H₂₂FN₆O₃:425.1737; found 425.1741. 88

Yield: 27%. ¹H-NMR (300 MHz,CDCl₃/MeOD) δ: 7.31-7.27 (2H, m), 7.00(2H,t, J=8.6 Hz), 4.53 (2H, s), 3.98 (4H,s), 2.98-2.84 (4H, m), 2.14 (2H,td, J=10.3, 5.4 Hz), 1.84 (2H, dd, J=12.8, 1.1 Hz).HRMS (M + H) calcdfor C₁₉H₂₂N₄O₄F:389.1625; found: 389.1610.

EXAMPLE 89

A mixture of example 18 (52 mg, 0.124 mmol) and mCPBA (64.2 mg, 0.372mmol) in CH₂Cl₂ was stirred at room temperature for 4 h. Then,concentrated and purified by preparative HPLC to afford example 89 (26.2mg, 47%) as a purple solid. ¹H NMR (500 MHz, CDCl₃) δ: 11.69 (1H, s),8.54 (1H, t, J=6.4 Hz), 7.75 (1H, dd, J=8.2, 2.7 Hz), 7.70 (1H, dd,J=8.6, 5.2 Hz), 7.34 (1H, td, J=7.9, 2.5 Hz), 4.81 (2H, d, J=6.7 Hz),3.99-3.94 (4H, m), 3.16 (3H, s), 2.21-2.16 (2H, m), 2.06-2.00 (2H, m),1.94-1.82 (4H, m). HRMS (M+H) calcd for C₂₀H₂₃FN₃O₆S: 452.1292; found:452.1286.

EXAMPLE 90

Example 90 was prepared according to the procedure for example 89 usingexample 39 to afford product in 38% as a purple solid. ¹H NMR (500 MHz,CDCl₃) δ: 11.82 (1H, bs), 8.57 (1H, t, J=5.8 Hz), 7.75 (1H, dd, J=8.0,2.6 Hz), 7.69 (1H, dd, J=8.4, 5.0 Hz), 7.33 (1H, td, J=7.9, 2.4 Hz),4.87-4.74 (2H. m), 4.20-3.98 (8H, m), 3.18 (3H, s), 2.61-2.56 (1H, m),2.34-2.29 (1H, m). HRMS (M+H) calcd for C₁₉H₂₁FN₃O₇S: 454.1084; found:454.1096.

EXAMPLE 91

A solution of intermediate 45 (0.096 g, 0.190 mmol) in dichloromethane(5 mL) and trifluoroacetic acid (5 mL) was stirred for 2 hours, and thensolvent was removed in-vacuo to give a yellow oil. The oil wastriturated with a minimal volume of 95% ethanol, and solids werecollected by filtration to give 91 (0.056 g, 71%) as a white solid aftervacuum pump drying: ¹H NMR (500 MHz, DMSO-D₆) δ: 12.19 (1H, s), 9.37(1H, t, J=6.4 Hz), 8.56-8.61 (1H, m), 7.44 (1H, dd, J=8.5, 5.8 Hz), 7.36(1H, dd, J=9.3, 2.6 Hz), 7.31 (1H, td, J=8.5, 2.6 Hz), 4.58 (2H, d,J=6.7 Hz), 3.92 (2H, t, J=5.3 Hz), 3.80 (2H, t, J=5.2 Hz), 2.79 (3H, d,J=4.6 Hz), 2.65-2.72 (2H, m), 2.19-2.25 (2H, m), 2.12-2.18 (1H, m),1.88-1.96 (1H, m). ¹³C NMR (126 MHz, DMSO-D₆) δ: 167.68, 161.68, 159.73,156.73, 150.37, 145.81, 137.24, 137.19, 132.61, 131.33, 131.27, 125.22,116.87, 116.70, 114.88, 114.70, 77.99, 57.88, 41.96, 40.33, 33.95,26.06, 13.08. HRMS (M+H) calc'd for C₂₀H₂₂N₄O₅F: 417.1574; found:417.1589.

EXAMPLE 92

Spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-.¹H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.82-1.91 (m, 2 H) 1.96-2.05 (m, 2H) 2.37 (d, J=7.32 Hz, 4 H) 2.88 (s, 3 H) 3.81 (t, J=6.41 Hz, 2 H)4.27-4.35 (m, 2 H) 4.58 (d, J=6.10 Hz, 2 H) 7.03-7.09 (m, 2 H) 7.29 (dd,J=8.55, 5.19 Hz, 2 H). ¹³C NMR (125 MHz, CHLOROFORM-D) δ 25.48, 25.67,37.53, 37.70, 39.57, 42.78, 46.18, 73.38, 115.99, 116.16, 125.28,129.41, 132.64, 146.79, 147.64, 157.41, 161.61, 167.67.

EXAMPLE 93

Spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-.¹H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.04 (d, J=5.19 Hz, 4 H) 2.38-2.46(m, 4 H) 2.82 (s, 3 H) 3.78 (t, J=6.26 Hz, 2 H) 4.28 (t, J=6.56 Hz, 2 H)4.44 (d, J=6.71 Hz, 12H) 7.14 (m, 1 H), 7.24 (m, 1 H), 7.74 (m, 1H),8.17 (s, 1 H), 8.51 (s, 1 H), 8.59 (m 1 H). ¹³C NMR (125 MHz,CHLOROFORM-D) δ 25.78, 37.50, 37.71, 39.19, 46.13, 73.32, 112.09,112.29, 117.19, 117.36, 125.50, 128.24, 134.76, 134.83, 144.05, 146.68,147.81, 152.56, 157.41, 161.33, 163.33, 167.59.

EXAMPLE 94

Spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-.¹H NMR (500 MHz, MeOD) δ ppm 1.94-2.03 (m, 2 H) 2.10 (m, 2 H) 2.47 (s, 3H) 2.65 (m, 2 H) 3.07 (s, 3 H) 3.92,(m, 2 H) 4.29 (t, J=6.41 Hz, 2 H)4.35-4.42 (m, 2 H) 7.36-7.42 (m, 2 H), 7.71 (m, 1), 8.10 (s, 1).

EXAMPLE 95

Spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-.¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41-1.69 (br m, 4 H), 2.08 (m, 2), 2.50(s, 3 H), 3.60 (m, 2), 3.91 (br m, 4 H), 4.05 (m, 2 H) 4.51 (d, J=6.10Hz, 2 H) 7.12-7.20 (m, 2 H) 7.33-7.39 (m, 2 H), 9.34 (m, 1 H), 12.37 (brs, 1 H).

EXAMPLE 96

Spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41-1.68 (br m, 4 H), 2.04 (br m 2),2.50 (s, 3 H) 3.46-3.56 (br m, 4 H), 3.90 (t, J=6.40, 2 H), 4.46 (d,J=6.10 Hz, 2 H) 7.43-7.54 (m, 1 H), 7.56-7.61 (m, 2 H), 8.27 (s, 1 H),9.01 (s, 1 H).

EXAMPLE 97

Spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-.¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.60-1.69 (br m, 4 H) 2.22 (br m, 2 H),2.35 (s, 3 H), 2.50 (s, 3 H), 3.60-4.04 (br m, 6 H), 4.26 (d, J=6.10 Hz,2 H), 7.47 (m, 1 H) 7.57 (td, J=5.95, 3.05 Hz, 2 H), 8.09 (s, 1 H), 9,08(m, 1 H), 12.06 (br s, 1 H).

EXAMPLE 98

Spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-.¹H NMR (500 MHz, DMSO-d,) δ ppm 1.80-1.87 (m, 1 H), 2.05-2.14 (m, 1 H)2.46-2.54 (m, 2 H), 2.50 (s, 3 H) 2.71 (s, 2 H) 3.53 (t, J=5.95 Hz, 2 H)3.95-4.04 (m, 2H) 4.53 (t, J=5.80 Hz, 2 H) 7.16-7.22 (m, 2 H) 7.37-7.43(m, 2 H), 9.36 (m, 1 H), 12.59 (br s, 1 H).

EXAMPLE 99

Spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-.¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.87-1.89 (m, 1 H), 2.11-2.15 (m, 1 H),2.50 (s, 3 H), 2.52-2.61 (m, 2 H) 2.74 (s, 2 H) 3.61 (t, J=5.80 Hz, 2H), 4.00 (d, J=5.49 Hz, 2 H) 4.48 (m, 2 H), 7.43 (m, 1 H) 7.59 (m, 2 H),8.29 (s, 1 H), 9.07 (s, 1 H), (9.27 (m, 1 H), 12.27 (br s, 1 H).

EXAMPLE 100

Spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.88-1.92 (m, 1 H), 2.10-2.16 (m, 1 H),2.36 (s, 3 H) 2.50 (s, 3 H) 2.58-2.62 (m, 4 H) 2.78 (br s, 2) 3.65 (t,J=6.10 Hz, 2 H) 4.03 (br s, 2 H) 4.27 (d, J=6.41 Hz, 2 H), 7.46-7.49 (m,1 H), 7.56-7.63 (m, 2 H), 8.08 (s, 1 H), 9.16 (m, 1 H), 12.31 (br s, 1H).

EXAMPLE 101

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR (400 MHz, CDCl₃) δ ppm: 11.95 (1 H, s), 8.80 (1 H, s), 7.92 (2 H,s), 7.76 (1 H, dd, J=8.6, 5.8 Hz), 7.20-7.27 (1 H, m), 7.11 (1 H, dd,J=8.5, 2.7 Hz), 4.46 (2 H, d, J=6.8 Hz), 3.95 (4 H, s), 2.69-2.78 (2 H,m), 2.27-2.38 (3 H, m), 2.27-2.38 (3 H, m), 2.03-2.14 (1 H, m), MS(ESI⁺) m/e 427 [M+H⁺], HRMS (ESI⁺) calculated for C₂₀H₂₀FN₆O₄[M+H⁺]427.1530; found: 427.1547.

EXAMPLE 102

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-1HNMR 400 MHz (CDCl₃) δ (ppm): 11.97 (1 H, s), 8.54 (1 H, m), 7.74 (1 H,dd, J=8.6, 5.8 Hz), 7.25-7.32 (1 H, m), 7.01 (1 H, dd, J=8.3, 2.5 Hz),4.30 (2 H, d, J=6.6 Hz), 3.95-4.02 (4 H, m), 2.73-2.82 (2 H, m),2.29-2.40 (6 H, m), 2.23 (3 H, s), 2.13 (1 H, m),.

EXAMPLE 103

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[2-[4-(1,1-dimethylethyl)-1H-1,2,3-triazol-1-yl]-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-¹H NMR (400 MHz, CDCl₃) δ ppm: 12.00 (1 H, s), 8.95-9.04 (1 H, m), 7.72(1 H, dd, J=8.6, 6.1 Hz), 7.61 (1 H, s), 7.19 (1 H, td, J=8.2, 2.8 Hz),7.11 (1 H, dd, J=8.7, 2.7 Hz), 4.50 (2 H, d, J=6.8 Hz), 3.95 (4 H, s),2.71-2.81 (2 H, m), 2.26-2.37 (3 H, m), 2.02-2.12 (1 H, m), 1.42 (9 H,s), MS (ESI⁺) m/e 483 [M+H⁺], HRMS (ESI⁺) calculated for C₂₄H₂₈FN₆O₄[M+H⁺]483.2156; found: 483.2179.

EXAMPLE 104

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-¹H NMR (400 MHz, CDCl₃) δ ppm: 11.90 (1 H, s), 8.49 (1 H, t, J=6.3 Hz),7.73 (1 H, dd, J=8.6, 5.8 Hz), 7.65 (1 H, s), 7.22-7.30 (1 H, m), 7.01(1 H, dd, J=8.3, 2.8 Hz), 4.26 (2 H, d, J=6.6 Hz), 3.95 (4 H, s),2.70-2.80 (2 H, m), 2.27-2.38 (6 H, m), 2.05-2.17 (1 H, m), LCMS (⁺ESI,M+H⁺) m/z 441.

EXAMPLE 105

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR 400 MHz (MeOD) δ (ppm): 7.56 (1 H, m), 7.22 (1 H, m), 7.12 (1 H,m), 4.59 (2 H, m), 4.10 (2 H, m), 3.99 (2 H, m), 3.90 (2 H, m), 2.80(2H, m), 2.80 (2H, m), 2.24 (2H, m), 2.13 (2 H, m), 2.02 (2 H, m). HRMS(ESI+) calculated for C₂₁H₂₂FN₄O₆ [M+H⁺]445.1523; found: 445.1506.

EXAMPLE 106

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(2-oxo-1-azetidinyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR 400 MHz (MeOD) δ (ppm): 7.61 (1 H, m), 7.04 (2 H, m), 4.65 (2 H,m), 4.01(2 H, m), 3.96 (2 H, m), 3.85 (2 H, m), 3.18 (2 H, m), 2.78 (2H, m), 2.31 (2 H, m), 2.21-2.02 (2 H, m). HRMS (ESI⁺) calculated forC₂₁H₂₂FN₄O₆ [M+H⁺]429.1574; found: 429.1561.

EXAMPLE 107

Spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-¹H NMR (400 MHz, CDCl₃) δ ppm: 12.02 (1 H, s), 8.34 (1 H, t, J=6.3 Hz),7.67 (1 H, dd, J=8.6, 5.8 Hz), 7.20-7.28 (1 H, m), 6.97 (1 H, dd, J=8.3,2.5 Hz), 4.36 (2 H, brs), 4.26 (2 H, d, J=6.6 Hz), 3.89 (2 H, t, J=5.7Hz), 2.79 (2 H, t, J=8.3 Hz), 2.39-2.48 (2 H, m), 2.35 (3 H, s), 2.18 (3H, s), 1.73-1.95 (4 H, m), LCMS (⁺ESI, M+H⁺) m/z 469.

EXAMPLE 108

Spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.A suspension ofN-(4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)-9-(chloromethyl)-3-hydroxy-9-(hydroxymethyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide(0.220 g, 0.459 mmol) and tetrabutyl ammonium bromide (0.075 g, 0.23mmol) in 1.0 N NaOH solution (2.5 mL) and water (2.5 mL) was heated (80°C., oil bath) for 4 hrs. The reaction was quenched with 1.0 N HClsolution (4 mL), and extracted into ethyl acetate (2×10 mL) and CH₂Cl₂(10 mL). The combined extracts were dried (Na₂SO₄), filtered, andconcentrated in-vacuo. The crude material was dissolved indimethylfomamide (3 mL) and purified by C-18 reverse phase columnchromatography, eluting with 10% -30% acetonitrile in water. Productfractions were concentrated to dryness by rotary evaporator, oroptionally reduced in volume and extracted with CH₂Cl₂. The product wasthen triturated with 95% ethanol or, optionally, AcCN. The resultingsolid was collected by filtration to give the title compound ascrystalline white solid: ¹H NMR (500 MHz, CDCl₃) δ ppm 12.38 (1H, s),8.84 (1H, t, J=6.41 Hz), 8.31 (1H, s), 7.70 (1H, dd, J=8.70, 5.95 Hz),7.17 (1H, td, J=8.24, 2.75 Hz), 7.08 (1H, dd, J=8.55, 2.44 Hz), 5.09(2H, d, J=6.41 Hz), 4.74 (2H, d, J=6.41 Hz), 4.51 (2H, d, J=6.71 Hz),4.01 (4H, s), 2.56 (3H, s); ¹³C NMR (126 MHz, CDCl₃) δ ppm 168.00,163.19, 161.23, 157.40, 147.55, 145.78, 144.02, 137.11, 137.03, 134.27,134.20, 128.33, 125.69, 116.59, 116.42, 111.99, 111.79, 81.76, 59.90,42.20, 39.37, 13.90; HRMS (ESI) calcd for C₂₀H₂₀N₆O₅F (M+H) 443.1479,found 443.1477, Elem. Anal. calcd for C₂₀H₁₉N₆O₅F.0.1 H₂O: C54.08, H4.36; N 18.92, found: C 54.04, H 4.07, N18.99.

EXAMPLE 109

Spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[(4-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-. ¹H NMR (500MHz, CDCl₃) δ ppm 12.30 (1H, s), 8.10 (1H, br), 7.29-7.36 (2H, m),7.02-7.08 (2H, m, J=8.55, 8.55 Hz), 5.02 (2H, d, J=6.41 Hz), 4.78 (2H,d, J=6.41 Hz), 4.61 (2H, d, J=6.41 Hz), 4.01 (4H, s); HRMS (ESI) calcdfor C₁₇H₁₇N₃O₅F (M+H) 362.1152, found 362.1148. HPLC purity: 98% AP(rt=1.92 min). White solid

EXAMPLE 110

Spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 12.10 (1H, s), 9.29 (1H, t, J=6.56 Hz),8.45 (1H, s), 8.36 (1H, s), 7.70 (1H, dd, J=8.70, 5.95 Hz), 7.21 (1H,td, J=8.16, 2.59 Hz), 7.10 (1H, dd, J=8.39, 2.59 Hz), 5.14 (2H, d,J=6.41 Hz), 4.79 (2H, d, J=6.71 Hz), 4.47 (2H, d, J=6.71 Hz), 4.00 (4H,s); ¹³C NMR (126 MHz, CDCl₃) δ ppm 167.62, 161.24, 157.40, 153.43,147.18, 145.97, 143.94, 134.27, 134.20, 128.63, 128.60, 125.85, 117.05,116.89, 112.79, 112.59, 82.18, 59.99, 42.17, 39.40; HRMS (ESI) calcd forC₁₉H₁₈N₆O₅F (M+H) 429.1323, found 429.1330. HPLC rt=1.60 min. Whitecrystalline solid

EXAMPLE 111

Spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 11.98 (1H, s), 8.78 (1H, t, J=6.56 Hz),7.76 (1H, dd, J=7.93, 2.75 Hz), 7.69 (1H, dd, J=8.55, 5.19 Hz), 7.34(1H, td, J=7.93, 2.75 Hz), 5.06 (2H, d, J=6.71 Hz), 4.88 (2H, d, J=6.71Hz), 4.77 (2H, d, J=6.71 Hz), 4.00 (4H, s), 3.22 (3H, s); ¹³C NMR (126MHz, CDCl₃) δ ppm 168.10, 163.08, 157.31, 147.33, 146.21, 140.79,134.57, 134.51, 132.73, 132.70 125.54, 121.50, 121.34, 117.64, 117.44,81.88, 59.93, 45.01, 42.15, 40.34; HRMS (ESI) calcd for C₁₈H₁₉N₃O₇FS(M+H) 440.0928, found 440.0937. Elem. Anal. calcd for C₁₈H₁₈N₃O₇FS.0.1CH₂Cl₂: C 48.53, H 4.10, N 9.38, found: C 48.29, H 3.79, N 9.33. HPLCrt=1.77 min. White solid

EXAMPLE 112

Spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-.¹H NMR 400 MHz (CDCl₃) δ (ppm): 11.94 (1 H, s), 8.55 (1 H, m), 7.98 (1H, s), 7.95 (1 H, s) 7.71 (1 H, dd, J=8.6, 5.8 Hz), 7.24-7.30 (1 H, m),7.16 (1 H, dd, J=8.3, 2.5 Hz), 4.51 (2 H, d, J=6.8 Hz), 4.05 (4 H, s),3.87-3.97 (2 H, m), 3.77-3.87 (2 H, m), 2.45 (2 H, td, J=13.2, 5.2 Hz),1.81 (2 H, d, J=13.6 Hz).

EXAMPLE 113

Spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR 400 MHz (CDCl₃) δ (ppm): 11.87 (1 H, s), 8.68 (1 H, m), 7.95 (1H,d, J=1.2 Hz), 7.94 (1 H, d, J=1.2 Hz), 7.76 (1 H, dd, J=8.6, 5.8 Hz),7.26 (1 H, dd, J=8.6, 2.5 Hz), 7.13 (1 H, dd, J=8.5, 2.7 Hz), 4.47 (2 H,d, J=6.8 Hz), 3.95-4.05 (4 H, m), 2.25-2.35(2 H, m), 2.00-2.11 (4 H, m),1.89(2 H, m).

EXAMPLE 114

Spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[(4-fluorophenyl)methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-.¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.85 (2H, m, CH₂), 2.05 (2H, m, CH₂), 2.3(2H, m, CH₂), 3.75 (2H, m, CH₂), 3.8-3.9 (4H, m, 2×CH₂), 4.5-4.7 (4H, m2×CH₂), 7.1 (2H, m, aromatics), 7.35 (2H, m, aromatics), 7.75 (1H, broadt, NH), 12.1 (1H, s, OH). MS (ESI⁺) m/e 404 [M+H⁺].

EXAMPLE 115

Spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-.White crystals; mp 211° C. (dec.) (ethyl acetate). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 1.87 (2H, m, CH₂), 1.99 (2H, m, CH₂), 2.43 (2H, m, CH₂), 3.05(3H, d, J=4.8 Hz, NCH₃), 3.72 (2H, m, CH₂), 3.8 -3.9 (4H, m, 2×CH₂),4.55 (2H, m, CH₂), 4.61 (2H, d, J=6.5 Hz, NCH₂), 6.24 (1H, m, NH), 7.15(1H, m, aromatic), 7.21 (1H, dd, J=2.7 Hz and J=8.6 Hz, aromatic), 7.52(1H, dd, J=5.4 Hz and J=8.6 Hz, aromatic), 9.00 (1H, broad t, NH), 12.18(1H, s, OH). MS (ESI⁺) m/e 461 [M+H⁺].

EXAMPLE 116

Spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-.White crystals; mp 257° C. (dec.) (ethanol). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.85 (2H, m, CH₂), 1.99 (2H, m, CH₂), 2.33 (2H, m, CH₂), 3.22(3H, s, SCH₃), 3.71 (2H, m, CH₂), 3.75-3.9 (4H, m, 2×CH₂), 4.56 (2H, m,CH₂), 4.85 (2H, d, J=6.8 Hz, NCH₂), 7.37 (1H, m, aromatic), 7.72 (1H,dd, J=5.0 Hz and J=8.6 Hz, aromatic), 7.78 (1H, dd, J=2.6 Hz and J=8.3Hz, aromatic), 8.55 (1H, broad t, NH), 11.87 (1H, s, OH). Anal. Calcdfor C₂₁H₂₄FN₃O₇S: C 52.38, H 5.02, N 8.72; Found: C 52.17, H 5.21, N8.44.

EXAMPLE 117

Phosphonic acid,[5-fluoro-2-[[[(2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxospiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepin]-2′-yl)carbonyl]amino]methyl]phenyl]-,dimethyl ester. White crystals; mp 234° C. (dec.) (ethyl acetate).¹HNMR400 MHz (CDCl₃) δ (ppm): 1.85 (2H, m, CH₂), 1.99 (2H, m, CH₂), 2.41 (2H,m, CH₂), 3.71 (2H, m, CH₂), 3.8-3.9 (4H, m, 2×CH₂), 3.86 (3H, s, OCH₃),3.88 (3H, s, OCH₃), 4.56 (2H, m, CH₂), 4.78 (2H, d, J=6.6 Hz, NCH₂),7.26 (1H, m , aromatic), 7.49 (1H, m, aromatic), 7.63 (1H, m, aromatic),9.02 (1H, broad t, NH), 12.18 (1H, s, OH). MS (ESI⁺) m/e 512 [M+H⁺].

EXAMPLE 118

Spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-.White crystals; mp 247° C. (dec.) (ethyl acetate). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 1.89 (2H, m, CH₂), 2.01 (2H, m, CH₂), 2.43 (2H, m, CH₂), 3.74(2H, m, CH₂), 3.8-3.9 (4H, m, 2×CH₂), 4.47 (2H, d, J=6.9 Hz, NCH₂), 4.56(2H, m, CH₂), 7.14 (1H, dd , J=2.5 Hz and J=8.6 Hz, aromatic), 7.24 (1H,m, aromatic), 7.72 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 8.31 (1H,s, CH), 8.49 (1H, s, CH), 9.01 (1H, broad t, NH), 11.99 (1H, s, OH). MS(ESI⁺) m/e 471 [M+H⁺]. Anal. Calcd for C₂₂H₂₃FN₆O₅.0.5 H₂O: C 55.11, H5.05, N 17.53; Found: C 55.17, H 4.91, N 17.02.

EXAMPLE 119

Spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-.White crystals; mp 240° C. (dec.) (ethyl acetate). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 1.86 (2H, m, CH₂), 2.01 (2H, m, CH₂), 2.37 (2H, m, CH₂), 2.61(3H, s, CH₃), 3.72 (2H, m, CH₂), 3.8-3.9 (4H, m, 2×CH₂), 4.51 (2H, d,J=6.9 Hz, NCH₂), 4.56 (2H, m, CH₂), 7.12 (1H, dd, J=2.5 Hz and J=8.6 Hz,aromatic), 7.20 (1H, m, aromatic), 7.72 (1H, dd, J=5.9 Hz and J=8.6 Hz,aromatic), 8.34 (1H, s, CH), 8.72 (1H, broad t, NH), 12.27 (1H, s, OH).MS (ESI⁺) m/e 485 [M+H⁺]. Anal. Calcd for C₂₃H₂₅FN₆O₅: C 57.02, H 5.20,N 17.35; Found: C 56.92, H 5.09, N 16.74.

EXAMPLE 120

Spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-.White crystals; mp 204° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.87 (2H, m, CH₂), 2.01 (2H, m, CH₂), 2.5 (2H, m, CH₂), 2.52 (3H,s, CH₃), 3.74 (2H, m, CH₂), 3.8-3.9 (4H, m, 2×CH₂), 4.32 (2H, d, J=6.6Hz, NCH₂), 4.56 (2H, m, CH₂), 7.05 (1H, dd, J=2.5 Hz and J=8.3 Hz,aromatic), 7.26 (1H, m, aromatic), 7.70 (1H, dd, J=6.1 Hz and J=8.6 Hz,aromatic), 8.14 (1H, s, CH), 8.76 (1H, broad t, NH), 11.96 (1H, s, OH).Anal. Calcd for C₂₃H₂₅FN₆O₅: C 57.02, H 5.20, N 17.34; Found: C 52.08, H5.35, N 17.21.

EXAMPLE 121

Spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,2,3,5,6,7,8′-hexahydro-3′-hydroxy-N-[[2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4′-oxo-.White crystals; mp 247° C. (dec.) (ethanol). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.86 (2H, m, CH₂), 2.0 (2H, m, CH₂), 2.38 (2H, m, CH₂), 2.61 (3H,s, CH₃), 3.73 (2H, m, CH₂), 3.85-3.9 (4H, m, 2×CH₂), 4.53 (2H, d, J=6.9Hz, NCH₂), 4.56 (2H, m, CH₂), 7.35-7.4 (1H, m, aromatic), 7.45-7.52 (2H,m, aromatics), 7.69-7.74 (1H, m, aromatic), 8.33 (1H, s, CH), 8.74 (1H,broad t, NH), 12.33 (1H, s, OH). Anal. Calcd for C₂₃H₂₆N₆O₅: C 59.21, H5.61, N 18.01; Found: C 59.46, H 5.50, N 17.80.

EXAMPLE 122

Spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-.White crystals; mp 239° C. (dec.) (ethyl acetate). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 1.90 (2H, m, CH₂), 1.99 (2H, m, CH₂), 2.45 (2H, broad m, CH₂),3.74 (2H, m, CH₂), 3.84-3.95 (4H, m, 2×CH₂), 4.48 (2H, d, J=6.8 Hz,NCH₂), 4.58 (2H, m, CH₂), 7.14 (1H, dd, J=2.5 Hz and J=8.6 Hz,aromatic), 7.26 (1H, m, aromatic), 7.73 (1H, dd, J=6.0 Hz and J=8.6 Hz,aromatic), 7.95 (1H, s, CH), 7.97 (1H, s, CH), 8.75 (1H, broad t, NH),11.97 (1H, s, OH). MS (ESI⁺) m/e 471 [M+H⁺].

EXAMPLE 123

Spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 12.24 (1H, s), 8.73 (1H, br), 8.35 (1H,br), 7.70 (1H, dd, J=8.55, 5.80 Hz), 7.15-7.22 (1H, m), 7.08 (1H, d,J=8.24 Hz), 4.49 (2H, d, J=6.71 Hz), 4.38 (2H, br), 3.89 (2H, t, J=5.34Hz), 2.80 (2H, br), 2.49 (3H, s), 2.39-2.47 (2H, m), 1.86-1.93 (1H, m),1.79-1.86 (2H, m), 1.68-1.75 (1H, m); ¹³C NMR (126 MHz, CDCl₃) δ ppm168.33, 163.20, 162.01, 158.53, 150.67, 147.81, 143.86, 136.80, 136.73,134.33, 134.26, 128.55, 124.54, 116.92, 116.76, 112.00, 111.80, 82.11,64.54, 40.77, 39.06, 32.00, 28.65, 13.88, 12.72; HRMS calcd forC₂₂H₂₄N₆O₄F (M+H) 455.1843, found 455.1849. HPLC rt=2.12 min. Whitecrystalline solid

EXAMPLE 124

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 12.18 (1H, s), 8.66 (1H, br m), 8.32 (1H,s), 7.69-7.75 (1H, m), 7.18 (1H, td, J=8.16, 2.59 Hz), 7.04-7.11 (1H,m), 4.51 (2H, d, J=6.71 Hz), 3.96 (4H, s), 2.64-2.72 (2H, m), 2.50 (3H,s), 2.30-2.38 (2H, m), 2.07-2.16 (1H, m), 2.00-2.07 (1H, m); ¹³C NMR(126 MHz, CDCl₃) δ ppm 168.33, 163.20, 162.01, 158.53, 150.67, 147.81,143.86, 136.80, 134.33, 134.26, 128.55, 124.54, 116.92, 116.76, 112.00,111.80, 82.11, 64.54, 40.77, 39.06, 32.00, 28.65, 13.88, 12.72; HRMScalcd for C₂₁H₂₂N₆O₄F (M+H) 441.1687, found 441.1679. HPLC rt=2.07 min.White crystalline solid

EXAMPLE 125

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,6′,7′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(2-oxo-1-azetidinyl)phenyl]methyl]-.¹H NMR (500 MHz, CDCl₃) δ ppm 12.28 (1H, br), 9.15 (1H, t,J=6.10 Hz),7.62 (1H, d, J=7.63 Hz), 7.32 (1H, t, J=7.63 Hz), 7.22 (1H, t, J=7.48Hz), 7.06 (1H, d, J=7.93 Hz), 4.64 (2H, d, J=6.71 Hz), 3.92-3.98 (4H,m), 3.76 (2H, t, J=4.43 Hz), 3.15 (2H, t, J=4.12 Hz), 2.67-2.74 (2H, m),2.25-2.32 (2H, m), 2.12-2.21 (1H, m), 1.96-2.05 (1H, m); ¹³C NMR (126MHz, CDCl₃) δ ppm 168.38, 165.98, 157.89, 150.28, 146.64, 136.09,132.30, 131.12, 128.84, 126.73, 126.17, 120.50, 78.90, 58.58, 42.47,39.88, 35.44, 34.68, 13.65; HRMS calcd for C₂₁H₂₃N₄O₅ (M+H) 411.1668,found 411.1682; Elem. Anal. calcd for C₂₁H₂₂N₄O₅: C 61.45, H 5.40, N13.65, found: C 61.43, H 5.56, N 13.62. HPLC rt=2.24 min. Whitecrystalline solid

EXAMPLE 126

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,6′,7′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-.¹H NMR (500 MHz, CDCl₃) δ ppm 12.14 (1H, s), 8.63 (1H, t, J=5.95 Hz),7.56 (1 H, d J=7.32 Hz), 7.32-7.40 (2H, m), 7.24-7.27 (1H, m), 4.61 (2H, d, J=6.41 Hz), 4.57 (2H, t, J=7.93 Hz), 4.07 (2H, t, J=7.93 Hz),3.92-3.99 (4H, m), 2.69 (2 H, ddd J=12.13,9.23, 6.10 Hz), 2.23-2.30 (2H,m), 2.08-2.17 (1H, m), 1.96-2.05 (1H, m); ¹³C NMR (126 MHz, CDCl₃) δ ppm168.35, 157.84, 157.49, 150.51, 146.66, 136.05, 135.17, 131.29, 129.20,128.71, 125.91, 125.20, 79.00, 62.62, 58.56, 48.12, 42.53, 38.96, 34.65,13.79; HRMS calcd for C₂₁H₂₃N₄O₆ (M+H) 427.1618, found 427.1616; Elem.Anal. calcd for C₂₁H₂₂N₄O₆: C 59.15, H 5.20, N 13.13, found: C 59.10, H4.99, N 13.26. HPLC rt=1.97 min. Crystalline solid

EXAMPLE 127

Spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 12.09 (1H, s), 8.36 (1H, t, J=6.26 Hz),7.68 (1H, dd, J=8.55, 6.10 Hz), 7.21 (1H, td, J=8.24, 2.44 Hz), 7.00(1H, dd, J=8.24, 2.44 Hz), 4.35 (2H, d, J=6.71 Hz), 3.96 (4H, br),2.65-2.72 (2H, m), 2.43 (3H, s), 2.42 (3H, s), 2.29-2.38 (2H, m),2.03-2.13 (2H, m); LC/MS m/z 455.04 (M+H). HPLC rt=1.87 min. Whitecrystalline solid

EXAMPLE 128

Spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide,N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR (500 MHz, CDCl₃) δ ppm 12.17 (1H, s), 8.44 (1H, t, J=6.26 Hz),7.67 (1H, dd, J=8.55, 5.80 Hz), 7.21 (1H, td, J=8.24, 2.75 Hz), 6.99(1H, dd, J=8.55, 2.44 Hz), 4.36-4.43 (2H, m), 4.33 (2H, d, J=6.41 Hz),3.90 (2H, t, J=5.49 Hz), 2.75-2.84 (2H, m), 2.46-2.40 (2H, m), 2.44 (3H,s), 2.41 (3H, s), 1.85-1.94 (1 H, m), 1.83 (2 H, dt, J=10.76, 5.46 Hz),1.65-1.74 (1 H, m); ¹³C NMR (126 MHz, CDCl₃) δ ppm 168.31, 160.95,160.48, 158.49, 153.70, 150.76, 147.81, 136.90, 133.38, 133.31, 130.81,124.43, 117.50, 117.33, 114.25, 114.06, 82.13, 64.54, 40.77, 38.62,31.96, 28.66, 13.77, 12.77, 12.68; HRMS (ESI) calcd for C₂₃H₂₆N₆O₄F(M+H) 469.2000, found 469.1999; Elem. Anal. calcd for C₂₃H₂₅N₆O₄F: C58.96, H 5.37, N 17.93, found: C 59.03, H 5.25, N 17.82. HPLC rt=1.91min. White crystalline solid

EXAMPLE 129

Spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.¹HNMR (500 MHz, CDCl₃) δ: 12.10 (1H, s), 8.55 (1H, t, J=6.1 Hz), 8.29(1H, s), 7.69 (1H, dd, J=8.5, 5.8 Hz), 7.17 (1H, td, J=8.2, 2.5 Hz),7.08 (1H, dd, J=8.5, 2.5 Hz), 4.47 (2H, d, J=6.7 HzO, 4.02-3.94 (4H, m),2.52 (3H, s), 2.23-2.16 (2H, m), 2.09-2.04 (2H, m), 1.88-1.83 (4H, m).HRMS (M+H) cald. for C₂₂H₂₄FN₆O₄: 455.1843, found: 455.1833. Elem. anal.calcd for C₂₂H₂₃FN₆O₄: C, 58.14, H, 5.10; N, 18.49; found: C, 57.98; H,4.92; 18.40.

EXAMPLE 130

Spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide,N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-.LC/MS m/z 469 (M+H). ¹H NMR (CDCl₃, 500 MHz) δ ppm 1.80-1.93 (4H, m, 11,CH₂), 2.00-2.13 (2H, m, CH₂), 2.14-2.25 (2H, m, CH₂), 2.41 (3H, s CH₃),2.42 (3H, s, CH₃), 3.93-3.98 (2H, m, OCH₂), 4.00 (2H, q, J=5.4 Hz,7-NCH₂), 4.31 (2H, d, J=6.7 Hz, CH₂), 6.99 (1H, dd, J=8.4, 2.6 Hz, CH),7.20 (1H, dt, J=8.5, 2.5 Hz, CH), 7.64 (1H, dd, J=8.5, 5.9 Hz, CH), 8.25(1H, t, J=6.4 Hz, NH), 12.00 (1H, s, OH). ¹³C NMR (CDCl₃, 125.8 Hz) δppm 12.7 (CH₃), 13.8 (CH₃), 24.5 (CH₂), 38.6 (NCH₂), 40.4 (CH₂), 42.9(NCH₂), 58.7 (OCH₂), 86.2 (C), 114.2 (d, J=24 Hz, CH), 117.3 (d, J=21Hz, CH), 125.6 (C), 130.8 (d, J=3.8 Hz, C), 133.2 (d, J=8.7 Hz, CH),137.0 (d, J=9.6 Hz, C), 146.4 (C), 151.5 (C), 153.8 (C), 157.8 (C),160.5 (C), 161.9 (d, J=250 Hz, CF), 168.2 (C═O). HRMS (ESI) calcd forC₂₃H₂₆FN₆O₄ (M+H) 469.2000, found 469.1990. UV (MeOH) λ max 317 nm(ε7.80×10³). Anal. calcd for C₂₃H₂₅FN₆O₄: C58.96, H5.37, N1 7.93; foundC58.69, H5.12, N17.95.

EXAMPLE 131

Spiro[cyclobutane-1,9′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-.¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.08 (m, 1 H) 2.15 (m, 1 H) 2.45-2.52(m, 2 H) 2.82-2.90 (m, 2 H) 3.53 (t, J=5.95 Hz, 2 H) 4.00 (t, J=5.80 Hz,2 H) 4.48 (d, J=6.41 Hz, 2 H) 7.43 (td, J=8.39, 2.44 Hz, 1 H) 7.55-7.62(m, 2 H) 8.31 (s, 1 H) 9.07 (s, 1 H) 9.28 (t, J=6.41 Hz, 1 H), 12.25(brs, 1 H).

EXAMPLE 132

Spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide,N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.05-2.14 (m, 2 H) 2.42-2.49 (m, 2 H) 2.92 (ddd,J=13.20, 9.23, 6.26 Hz, 2 H) 3.53 (t, J=5.95 Hz, 2 H) 4.02 (t, J=6.10Hz, 2 H) 4.53 (d, J=6.41 Hz, 2 H) 7.18 (t, J=9.00 Hz, 2 H) 7.39 (dd,J=8.55, 5.49 Hz, 2 H) 9.45 (t, J=6.41 Hz, 1 H), 12.54 (brs, 1 H).

1. A compound of Formula I selected from the group consisting ofN-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclopentane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4-oxo-spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclohexane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8′-methyl-4-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-8-methyl-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[2-[4-(1,1-dimethylethyl)-1H-1,2,3-triazol-1-yl]-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[4-fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[4-fluoro-2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[4-fluoro-2-(2-oxo-1-azetidinyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[2-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[(4-fluorophenyl)methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[oxetane-3,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-2,3,5,6,6′,7′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[(4-fluorophenyl)methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-[(methylamino)carbonyl]phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-(methylsulfonyl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;[5-fluoro-2-[[[(2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxospiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepin]-2′-yl)carbonyl]amino]methyl]phenyl]-phosphonicacid, dimethyl ester;N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;2,3,5,6,7′,8′-hexahydro-3′-hydroxy-N-[[2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]methyl]-2,3,5,6,7′,8′-hexahydro-3′-hydroxy-4′-oxo-spiro[4H-pyran-4,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;6′,7′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(2-oxo-1-azetidinyl)phenyl]methyl]-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;6′,7′-dihydro-3′-hydroxy-4′-oxo-N-[[2-(2-oxo-3-oxazolidinyl)phenyl]methyl]-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,10′(4′H)-[6H]pyrimido[2,1-c][1,4]oxazepine]-2′-carboxamide;N-[[4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]methyl]-6′,7′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclopentane-1,9′(4′H)-pyrimido[2,1-c][1,4]oxazine]-2′-carboxamide;N-[[4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl]methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;andN-[(4-fluorophenyl)methyl]-7′,8′-dihydro-3′-hydroxy-4′-oxo-spiro[cyclobutane-1,9′(6′H)-[4H]pyrazino[1,2-a]pyrimidine]-2′-carboxamide;or a pharmaceutically acceptable salt or solvate thereof.
 2. Acomposition comprising a therapeutic amount of a compound of claim 1 anda pharmaceutically acceptable carrier.
 3. A method of inhibiting HIVintegrase comprising contacting a compound of claim 1 with HIVintegrase.
 4. A method of inhibiting HIV viral DNA integration intohuman DNA comprising administering an effective amount of a compound ofclaim 1 to a patient infected with HIV.
 5. A method for treating HIVinfection comprising administering a therapeutically effective amount ofa compound of claim 1, or a pharmaceutically acceptable salt or solvatethereof, to a patient infected with HIV.
 6. The method of claim 5,further comprising a therapeutically effective amount of one or moreother HIV treatment agents selected from the group consisting of HIVprotease inhibitors, HIV nucleoside reverse transcriptase inhibitors,HIV non-nucleoside reverse transcriptase inhibitors, HIV-entryinhibitors, HIV integrase inhibitors, immunomodulators, or a combinationthereof.